Even 'high normal' glucose levels may increase the risk of hospitalization for heart failure

Drawing on data from 31,546 high-risk patients participating in two international trials, researchers found that even small increases in fasting glucose raised the risk of congestive heart failure in both diabetes patients and those whose blood sugar fell within the normal range.

“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 Claes Held, M.D., Ph.D., lead author of the study.

“However, these are only associations,” said Held, an associate professor of cardiology at the Karolinska Institutet in Stockholm, Sweden. “They do not prove that elevated blood glucose causes heart failure. To demonstrate a causal relationship, you would have to do a study that showed lowering blood glucose levels would reduce the incidence of heart failure.”

About 5.2 million Americans evenly divided between males and females suffer from heart failure, according to the American Heart Association. Each year about 550,000 new cases are diagnosed and about 57,700 people die from it. Heart failure is a debilitating condition in which the heart fails to pump an adequate supply of blood throughout the body. Established heart failure risks include uncontrolled high blood pressure, diabetes and heart attack.

To examine the relationship between blood glucose levels and congestive heart failure, Held and colleagues performed an interim analysis on the blinded data from the ONgoing Telmisartan Alone and in combination with the Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease (TRANSCEND) trials. Both were randomized, controlled, parallel clinical studies testing drug regimens aimed at reducing fatal and nonfatal cardiovascular events. ONTARGET had 25,620 patients enrolled and TRANSCEND had 5,926, and both included patients with and without diabetes. Researchers obtained fasting blood glucose levels for patients when they entered the trials and periodically thereafter.

“We know that diabetes is a strong risk factor for cardiovascular disease including heart failure, but these studies included patients with and without diabetes,” Held said. “This was a great opportunity to evaluate a broad population of high-risk individuals and study the association between blood glucose and cardiovascular disease, regardless of the diabetic state.”

Patients in the two trials were average age 67 at entry, and 69 percent were men. Thirty-seven percent had been previously diagnosed with diabetes and 3.2 percent were diagnosed with the disease at the time of entry.

Patients were assigned to five groups based on their entry fasting blood glucose levels, measured in millimoles per liter of blood, or mmol/L. The lowest group had an average fasting blood glucose of 4.6 mmol/L and the highest had an average reading of 8.5 mmol/L.

The mmol/L is the international standard unit for measuring blood glucose. In the United States, blood glucose levels are usually reported in milligrams per deciliter, mg/dL. Multiplying the number of mmol/L by 18 converts the number to mg/dl.

Researchers analyzed data from patients with an average follow-up of 2.4 years. During this time there were:

1,067 cardiovascular deaths
926 heart attacks
823 strokes
668 hospitalizations for congestive heart failure
When the researchers examined fasting blood glucose levels alone as a risk factor by adjusting for other known risk factors, they found that, for all patients, an increase of 1 mmol/L above a patient's entry glucose level increased the risk of hospitalization for congestive heart failure by 5 percent.

Similarly, a 1 mmol/L rise increased the risk of congestive heart failure hospitalization or cardiovascular death by 9 percent for all patients, by 3 percent for patients without diabetes and by 5 percent for patients with diabetes.

“Even in the normal range, our results indicate that elevated blood glucose is associated with the risk of heart failure,” Held said. “You can look at blood glucose much like blood pressure or cholesterol. 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.”

He and colleagues suggested several potential mechanisms for rising glucose levels which increase the risk of developing congestive heart failure.

“Individuals with disturbances in their glucose regulation usually have more coronary artery disease, which is a well known underlying risk factor for heart failure,” Held said. “That is a strong explanation for our findings but the others are more speculative and hypothetical.”