Adding evolocumab to both moderate- and high-intensity statin therapy lowered low-density lipoprotein cholesterol even further in an international phase III clinical trial reported online May 13 in JAMA.
Evolocumab, a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), showed robust LDL cholesterol–lowering properties in preliminary studies and was well tolerated. In this industry-sponsored, phase III trial, evolocumab significantly reduced LDL cholesterol (LDL-C) in a substantially larger portion of patients, compared with both placebo and additive ezetimibe, with comparable rates of adverse events, said Dr. Jennifer G. Robinson, who is professor of both epidemiology and medicine as well as director of the lipid research clinic and codirector of the prevention intervention center at the University of Iowa College of Public Health, Iowa City, and her associates.
This is the first study to demonstrate that adding evolocumab allows most (86%-94%) patients to achieve LDL-C levels of less than 70 mg/dL regardless of background statin type or dose, they noted.
The double-blind trial involved 1,899 adults up to 80 years of age (mean age, 60 years) residing in Australia, Belgium, Canada, the Czech Republic, Denmark, France, Germany, Hong Kong, Hungary, Italy, the Netherlands, Russia, Spain, Sweden, Switzerland, the United Kingdom, and the United States. At enrollment, 29% were already taking intensive statin therapy, 41% were taking nonintensive statin therapy, and 30% were not taking statins.
Nearly half of the study participants were women; 23% had coronary artery disease, 10% had other atherosclerotic cardiovascular disease, and 16% had diabetes mellitus. These participants were randomly assigned to 1 of 24 treatment groups for 12 weeks, in which they took oral atorvastatin, rosuvastatin, or simvastatin in a variety of doses, plus either subcutaneous evolocumab or placebo injections on different schedules or oral ezetimibe or oral placebo.
Every group of patients who received additive evolocumab, whether at dosing every-2 weeks or at monthly dosing, showed significant lowering of LDL-cholesterol beyond what was achieved with background statin therapy. Compared with placebo, the reduction from baseline LDL-cholesterol level ranged from 66% to 75%.
In comparison, the reduction from baseline with ezetimibe never exceeded 24%.
With additive evolocumab, 86%-94% of patients achieved LDL-cholesterol levels of less than 70 mg/dL. In contrast, only 17%-62% of patients receiving additive ezetimibe achieved such low levels, Dr. Robinson and her associates said (JAMA 2014;311:1870-82).
Adding evolocumab also improved non–high-density lipoprotein cholesterol, lipoprotein(a), apolipoprotein B, triglyceride, and HDL-cholesterol profiles, beyond the benefits of statin therapy alone.
The rates of adverse events that lead to discontinuation of the study drug were 1.9% with evolocumab, 1.8% with ezetimibe, and 2.2% with placebo, and the rates of serious adverse events were 2.1%, 0.9%, and 2.3%, respectively.
The next step in assessing evolocumab will be to determine whether these lowering of LDL cholesterol levels translate into reductions in atherosclerotic CVD events. And, given the short-term duration of treatment in this trial, future research also must address longer-term safety and clinical outcomes, the investigators said.