Beta-blockers have a significant beneficial effect on survival in patients with heart failure. However, recent investigations show not all beta-blockers have the same effect in these patients.

Recently, the COMET trial compared the beta-1 selective agent metoprolol succinate against carvedilol, the combined adrenergic blocking agent. Carvedilol has not only beta-1 blocking properties, but also beta-2 and alpha-1 blocking properties. Results of the COMET trial suggest carvedilol is superior to metoprolol succinate with respect to mortality.

Dr. Shannon and colleagues wanted to determine why these two agents might have differential effects in heart failure patients. These researchers have focused on metabolic abnormalities that occur in heart failure. In particular, they have found that in failing heart preferentially uses glucose as its myocardial metabolic substrate. Therefore, they were interested in whether different beta-blockers have differential effects on myocardial glucose uptake.

To compare the effects of these two beta-blockers, researchers used rapid pacing for 29 days to induce severe dilated cardiomyopathy in 13 chronically instrumented adult dogs.

Researchers then randomized the dogs to receive carvedilol (Coreg) 25 mg bid or metoprolol succinate (Toprol XL) 100 mg qd for 3 days. They chose these doses in order to match heart rate effects for the two drugs.

Researchers took hemodynamic and metabolic measurements before treatment and on the final day of treatment. They measured myocardial glucose uptake as the product of coronary blood flow and transmyocardial substrate balance.

Hemodynamic effects

Researchers found that complete adrenergic blockade with carvedilol had a significantly greater effect on hemodynamics. Carvedilol lowered cardiac filling pressures, and improved cardiac output to a greater extent than metoprolol. This occurred despite the fact the matched heart rate effects for carvedilol versus metoprolol.

Metabolic effects

Following treatment with carvedilol, plasma insulin levels rose nearly three-fold. As a result, there was a marked improvement in myocardial glucose uptake. By contrast, metoprolol succinate had no effect on basal insulin levels, nor did it have an effect on glucose uptake.

Effects on Glucoregulatory Hormones

In an attempt to understand the mechanism of improvement in myocardial glucose uptake, investigators measured the effect of these two beta-blockers on plasma levels of norepinephrine, a counter-regulatory hormone to the action of insulin. Researchers found that carvedilol suppressed plasma norepinephrine levels to a greater extent than metoprolol succinate.

Researchers also looked at effects of glucagon, a specific hormone that antagonizes the action of insulin. They demonstrated that carvedilol suppressed plasma glucagon levels, whereas metoprolol succinate did not.

Taken together, researchers believe that one the beneficial effects of combined adrenergic blockade with carvedilol is the improvement in metabolic utilization of glucose in the failing heart. The mechanism appears to involve suppression of norepinephrine and glucagon, which are key counter-regulatory hormones to the action of insulin. These mechanistic data may provide insight into why carvedilol was superior to metoprolol succinate in the COMET study.