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NEW ORLEANS -- PCSK9 inhibitor treatment atop statins regressed atherosclerotic plaque in an apparently dose-dependent manner, even at extremely low LDL levels, the GLAGOV trial showed.

Percent atheroma volume as measured by intravascular ultrasound (IVUS) dropped 0.95% with evolocumab (Repatha) compared with an increase of 0.05% with placebo over 78 weeks (P<0.001), , of the Cleveland Clinic, reported here at the American Heart Association meeting and simultaneously online in the Journal of the American Medical Association.

"The finding of 1% difference between groups of GLAGOV is really quite profound and we think will be clinically relevant," said lead author , also of the Cleveland Clinic, pointing to his group's prior findings on the of a 0.5% difference in disease progression.

Normalized total atheroma volume decreased by 5.8 mm³ with the monoclonal antibody but by 0.9 mm³ in the placebo group still getting what Nissen called "good statins" (P<0.001). Evolocumab induced plaque regression in 64.3% of patients compared with 47.3% seeing regression on placebo.

In an exploratory analysis in people already at 70 mg/dL or below at baseline, the LDL drop down to a mean 24 mg/dL on evolocumab still cut percent atheroma volume by 1.97% compared with 0.35% in the placebo group (P<0.0001).

"I thought there might be diminishing returns at low levels, but we don't see that," Nissen said at a press conference for the late-breaking clinical trials session.

Rather, the trial showed a continuous reduction in percent atheroma volume in nearly a straight line down to those low LDL levels.

"We were taught in medical school that a normal cholesterol was any total cholesterol level less than 300.... Over four decades we have gotten more and more evidence that going to lower levels produces benefit," he said. "So while we await the outcomes trials, GLAGOV is really the first intriguing evidence that clinical benefits may extend to LDL levels as low as 20 mg/dL."

"Strictly speaking, we still don't know for sure how changes in IVUS relate to clinical events," commented , of the University of Pennsylvania in Philadelphia. "But it certainly does support the idea that I believe in, that the lower you get the LDL the better."

Rader agreed that the GLAGOV findings make a positive result of the ongoing clinical outcomes trials more likely. If so, he said, "I predict we are going to enter into a new phase where we're going to start really targeting very low levels of LDL again with the idea that's how you reduce risk as much as possible."

As a surrogate, IVUS has a fairly good record of prediction for clinical outcomes. Nissen noted that the GLAGOV population was similar to that of the FOURIER outcomes trial.

GLAGOV included 968 patients getting cardiac catheterization for angiographic coronary disease, who were on optimized background statin therapy and randomized to double-blind treatment with evolocumab (420 mg monthly) or placebo subcutaneous injections. The mean LDL level at baseline was 92 mg/dL, with 98% on a statin and about 60% on a high-intensity statin.

While evolocumab was approved in 2015 for adults who fail to achieve LDL cholesterol lowering through diet and maximally-tolerated statin therapy, including patients with heterozygous or homozygous familial hypercholesterolemia (FH), the high price of the PCSK9 inhibitors has meant difficulty getting prescription reimbursement authorized.

It wasn't clear how many of the participants in GLAGOV had FH, but the implications for plaque regression should apply across the spectrum, Nissen suggested.

"If you believe in the LDL hypothesis -- and I happen to believe in it -- LDL is LDL," he told 番茄社区 at the press conference. "If you scale [the results] up to the somewhat higher LDLs of FH patients, I have every reason to believe the benefits would be even greater."

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