The PCSK9 inhibitor evolocumab produced unequivocally greater reductions in atherosclerosis volume as measured by intravascular ultrasound (IVUS) compared with placebo in patients receiving optimized background statin therapy. That’s the word from a presentation of results from the multicenter GLAGOV trial — the first IVUS study of a PCSK9 inhibitor — at the American Heart Association’s Scientific Sessions 2016.
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“While we await the definitive outcome trials of evolocumab, this study provides very strong evidence that reducing LDL cholesterol to unprecedentedly low levels can reverse disease progression,” says Cleveland Clinic Cardiovascular Medicine Chairman Steven Nissen, MD, who chaired the GLAGOV study and presented the findings. “Although atherosclerosis volume is still a surrogate end point, it presages what the morbidity and mortality trials are likely to show.”
The study was simultaneously published online by JAMA.
GLAGOV enrolled 968 patients at 197 centers around the world with symptomatic coronary artery disease who underwent coronary angiography showing 20 to 50 percent stenosis in a target vessel. All patients were on optimized statin therapy (high-intensity in 59 percent of patients) with a baseline LDL cholesterol (LDL-C) level either greater than 80 mg/dL or 60 to 80 mg/dL with additional high-risk features. They were randomized to 18 months of add-on therapy with evolocumab (420 mg monthly) or placebo given subcutaneously.
Trial coordination was conducted by the Cleveland Clinic Coordinating Center for Clinical Research (C5 Research).
After 18 months of therapy, mean LDL-C was 93.0 mg/dL in the statin monotherapy group (3.9 percent reduction from baseline) versus 36.6 mg/dL in the statin + evolocumab group (59.8 percent reduction from baseline). “No one’s ever reached levels that low in a clinical trial,” notes Dr. Nissen.
Those reductions translated to the following mean changes in percent atheroma volume, the study’s primary end point:
The between-group difference was statistically significant at the P < .0001 level, which was also the case for the secondary end point of change in total atheroma volume. Moreover, 64.3 percent of patients showed regression in percent atheroma volume in the statin + evolocumb group, versus 47.3 percent of those in the statin monotherapy group (P < .0001).
There were no differences in any adverse event rates — including muscle effects, neurocognitive effects or new-onset diabetes — between the groups. “No safety issues arose at these very, very low LDL levels,” says Dr. Nissen.
About one-quarter of patients in the trial had baseline LDL-C levels below 70 mg/dL, the most aggressive target in any dyslipidemia guidelines.
An exploratory analysis in this subgroup showed that statin + evolocumab therapy reduced mean LDL-C to 24.0 mg/dL and to a trough of 15.0 mg/dL. These reductions in the subgroup corresponded to a mean reduction in percent atheroma volume of 1.97 percent (P < .0001 vs. baseline and vs. the statin monotherapy group). Additionally, 81.2 percent of statin + evolocumab recipients in this subgroup showed atheroma regression over the course of the study. “That’s an extent of regression greater than we have ever seen before,” says Dr. Nissen.
He adds that a post hoc analysis showed statin + evolocumab therapy continued to have incremental benefit in atheroma regression at LDL-C levels as low as 20 mg/dL. “We found no level at which the incremental benefit of further LDL reduction was not present,” he says. “Just as people say you can never be too rich or too thin, it appears possible that you can never have too low an LDL cholesterol. This is pushing the envelope in terms of what we recognize a normal cholesterol level may be.”
Dr. Nissen notes that the study has limitations, including the fact that 13 percent of the initial 968 patients were lost to follow-up. And of course there’s the need for results of PCSK9 inhibitor outcome studies — the first of which are expected in April 2017 — before evidence of clinical benefit is definitive.
That said, he’s hopeful: “Over the past four decades, evidence has accumulated suggesting that optimal LDL levels for patients with coronary disease may be much lower than commonly achieved. The GLAGOV trial provides further intriguing supportive evidence while we await the outcome trials.”