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Long-term exposure to a PCKS9 inhibitor didn't lessen the impact on LDL or increase adverse events, researchers reported in one study, while another showed that very low LDL levels were safe long term and cut cardiac risk.

Among 1,255 patients randomized to evolocumab (Repatha) in one of five phase II studies (GAUSS-1, RUTHERFORD-1, YUKAWA-1, MENDEL-1, or LAPLACE-TIMI 57), and followed-up for an average of 44 months in the OSLER-1 extension study, the median LDL reduction over baseline in the original studies.

"To our knowledge, these 4,641 patient-years of follow-up represent the longest and most extensive experience reported to date for evolocumab or any other PCSK9 inhibitor," , of Florida's Jacksonville Center for Clinical Research, and colleagues wrote online in JAMA Cardiology.

Safety also appeared to be maintained in the open-label follow-up, albeit with the limitations of the evidence such selection bias-prone studies can provide.

"The annual frequency of adverse events did not occur more frequently with cumulative exposure during open-label observation," Koren's group wrote, which was true for adverse events of special interest as well, such as new-onset diabetes, muscle complaints (which actually decreased over time), and neurocognitive events.

There were no neutralizing antibodies to evolocumab detected. And the 79% persistence on evolocumab over the 44-month follow-up spoke to tolerability as well, Koren's group wrote, noting it "compares favorably with published data for adherence to other therapies including statins."

An accompanying editorial by , of Northwestern University in Chicago, agreed that the lack of significant levels of measured neutralizing antibodies was reassuring, although he cautioned about the "not large" sample size.

"The adherence achieved in this open-label extension study is adequate, but it should be noted that participants were shielded from the current high cost of these drugs," he added. "It is hoped that if outcome trial data are shown to be beneficial, cost will not be a limiting factor for those who would have the largest incremental benefit."

While OSLER-1 follow-up showed a median LDL of 60 mg/dL on long-term evolocumab, the second study -- a prespecified analysis of the intensive lipid-lowering IMPROVE-IT trial -- looked at the safety of levels below 30 mg/dL.

"Patients achieving an LDL-C level less than 30 mg/dL at 1 month had a over a 6-year period compared with patients achieving higher LDL-C concentrations," , of Brigham and Women's Hospital in Boston, and colleagues reported online in JAMA Cardiology.

Specifically, achieved LDL level did not significantly correlate after multivariate adjustment with the prespecified safety events of adverse events leading to drug discontinuation; adverse muscle, hepatobiliary, and neurocognitive events; and hemorrhagic stroke, heart failure, cancer, and noncardiovascular death.

For those reaching an LDL under 30 mg/dL at 1 month in the trial, the adjusted risk of the primary efficacy composite of cardiovascular death, major coronary events, or stroke was a relative 21% lower over 6 years (P=0.001) compared with an LDL of 70mg/dL or greater.

In the main randomized trial results, the addition of ezetimibe (Vytorin) to simvastatin (Zocor) cut median LDL to 54 mg/dL versus 70 mg/dL and reduced the rate of cardiovascular death, MI, or stroke to 32.7% versus 34.7% on simvastatin alone over 7 years in patients with a recent acute coronary syndrome.

"Several important negative findings are worthy of mention, including the lack of association between low LDL-C level and cancer, hemorrhagic stroke, and noncardiovascular death after multivariate adjustment," the researchers noted, adding that prior observational reports of such links "may represent associations without causality or even possibly reverse causality in patients with systemic illness that result in very low LDL-C concentration, rather than causally related events due to lower LDL-C achieved with lipid-lowering therapy."

"Intensive lipid-lowering therapy following acute coronary syndrome to levels well below current guideline recommendations is safe and more effective than the current target of 70mg/dL," they concluded.