ATLANTA — The ezetimibe/simvastatin combination pill Vytorin has a markedly greater anti-inflammatory effect, as reflected in C-reactive protein-lowering, than either agent alone, Dr. Christie M. Ballantyne said at the annual meeting of the American College of Cardiology.
It's already established that Vytorin produces greater low density lipoprotein (LDL) reductions than does statin monotherapy.
In an effort to learn more about the combination agent's effect on C-reactive protein (CRP)—an emerging risk factor for cardiovascular disease—Dr. Ballantyne and coinvestigators conducted a post hoc pooled analysis of three multicenter, randomized, double-blind, placebo-controlled clinical trials.
The pooled analysis included 3,083 patients with baseline LDL of 145–250 mg/dL who were randomized to 12 weeks of placebo, ezetimibe at 10 mg/day, various doses of Vytorin comprised of ezetimibe 10 mg plus simvastatin 10–80 mg, or simvastatin monotherapy at 10–80 mg/day.
Ezetimibe alone wasn't significantly more effective than placebo at lowering CRP levels. In combination with the various doses of simvastatin, however, it reduced CRP by a mean of 31%, compared with 14.3% in the pooled simvastatin monotherapy group, reported Dr. Ballantyne, professor of medicine at Baylor College of Medicine, and director of the Center for Cardiovascular Disease Prevention at Methodist DeBakey Heart Center, Houston.
Simvastatin monotherapy lowered LDL by a mean of 38%, while Vytorin dropped it by 52.5%, he added.
The CRP cutpoint associated with reduced cardiovascular event rates in previous studies has been 2 mg/dL. In the pooled analysis, 47.7% of Vytorin-treated patients achieved both an LDL of less than 100 mg/dL and a CRP below 2 mg/dL, as did a collective 22.2% of patients on simvastatin monotherapy. The more stringent target of an LDL below 70 mg/dL plus a CRP of less than 2 mg/dL was met by 21.6% of the Vytorin group and 3.2% of patients on simvastatin alone.
That said, Dr. Ballantyne was quick to add that the clinical significance of reducing CRP in patients at increased cardiovascular risk has yet to be established and is the subject of ongoing randomized prospective investigations.
Audience members inquired as to the mechanism underlying the apparent synergy between ezetimibe and simvastatin in robustly lowering CRP, an especially striking effect given ezetimibe's trivial impact as monotherapy.
“That's a good question. I wish I had the answer,” Dr. Ballantyne replied. Hypotheses abound.
One such hypothesis is that there is an as-yet unidentified key interaction between the inhibition of cholesterol absorption by ezetimibe and the statin's 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition.
It's noteworthy that no enhancement of CRP-lowering was seen in a study in which ezetimibe was combined with fenofibrate rather than a statin, he added.
Dr. Ballantyne is a consultant to Merck/Schering-Plough, which markets Vytorin.