PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibition is showing significant promise in reducing cardiovascular (CV) events with effective cholesterol-lowering, based on impressive results from the OSLER-1 and -2 (Open-Label Study of Long-Term Evaluation Against LDL-C) trials.

OSLER-1 and -2 showed that the investigational PCSK9-inhibitor evolocumab (Repatha, Amgen) along with standard therapy, reduced LDL-cholesterol (LDL-C) by 61 percent vs standard therapy alone; from a median 120 mg/dL to 48 mg/dL after a median 11.1 month follow-up (p<0.001). [N Engl J Med 2015, e-pub 15 March, doi:10.1056/NEJMoa1500858]

In a prespecified exploratory analysis, evolocumab also reduced the incidence of CV events, defined as death, MI, unstable angina, coronary revascularization, stroke, transient ischemic attack, or heart failure, at 1 year (0.95 percent) vs standard therapy alone (2.18 percent) (p=0.003). This 53 percent reduction with evolocumab was consistent across each major CV event.

“The reduction in LDL-C was profound and that may be why we saw a marked reduction in CV events so quickly,” said Dr. Marc Sabatine of the Brigham and Women’s Hospital in Boston, MA, USA, a TIMI (Thrombolysis in Myocardial Infarction) Study Group investigator and lead author of OSLER-1 and -2.

“It suggests that if we can drive a patient’s LDL-C down a large amount to a very low level, we may start to see a benefit sooner than would be expected with a more modest intervention.”

These results follow similar results with the PCSK9-inhibitor alirocumab (Praluent, Sanofi/Regeneron), presented earlier at the 2015 European Society of Cardiology Congress, which showed a 61 percent reduction in LDL-C vs a 1 percent increase with placebo (p<0.0001). [N Engl J Med 2015, e-pub 15 March, doi:10.1056/NEJMoa501031]

“We now have many studies in a variety of different populations where we’ve seen the ability of these drugs to significantly reduce LDL-C,” said Sabatine. “And all the data we have point to the fact that the reduction in clinical events is tied to the reduction in LDL-C.”

In the open-label OSLER trials, 4,465 patients who had participated in 1 of 12 previous parent trials of evolocumab were randomized to receive intravenous evolocumab 140 mg every 2 weeks or 420 mg monthly plus standard therapy or standard therapy alone.

Adverse events occurred similarly between the two arms, however, evolocumab was associated with slightly more neurocognitive events.

An ongoing trial to study the effect of evolocumab on CV outcomes is expected to answer key questions regarding its clinical potential. The study, involving 27,500 patients, is not expected to see results until 2017.