GLAGOV: Evolocumab Shows Atheroma Reduction on Top of Statins

November 15, 2016

NEW ORLEANS, LA — Addition of evolocumab (Repatha, Amgen), a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, to statin therapy produced significant atheroma regression and a continuous benefit with LDL-C levels right down to as low as 20 mg/dL in a new study[1].

The Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) trial was presented here today at the American Heart Association 2016 Scientific Sessions by study chair Dr Steven Nissen (Cleveland Clinic, OH) and simultaneously published online in the Journal of the American Medical Association.

Nissen said: "While we have to wait for the clinical-outcome studies to know for sure, we think this [intravascular ultrasound] IVUS trial is a signal of the benefit that can be achieved with very low levels of LDL-C.

"This is the first time we have looked at what happens in the artery at such low levels of LDL-C, and I think we can say the GLAGOV study provides intriguing evidence that the clinical benefits of lowering LDL can extend to levels as low as 20 mg/dL."

The study showed an average reduction of approximately 1% in atheroma volume after 18 months of treatment with evolocumab added to statin therapy, and about two-thirds of patients showed plaque regression.

Study discussant Dr Raul Santos (InCor University of San Paulo, Brazil) stated: "This study confirms the role of LDL-C in atherosclerosis modification and suggests we are at the start of a new era in lipid management."

He added: "These are the lowest LDL levels seen in any IVUS study to date, and they are associated with a 1% reduction in atheroma volume on top of statins. Those patients with lower baseline and on-treatment levels showed an even greater benefit on plaque regression."

"However, 35% of patients still had atheroma progression even on evolocumab, suggesting factors other than LDL may be involved," he continued.

Asked what the clinical benefit of a 1% reduction in atheroma volume may be, GLAGOV principal investigator Dr Stephen Nicholls (University of Adelaide, Australia) said that his group reported in a paper published in 2010 that a reduction in atheroma volume of 0.5% does have an effect on whether a patient has an event or not.

"So we believe this 1% reduction is quite profound and clinically relevant, but we will have to wait for the outcome trials to know for sure," he said.

During his presentation, Nissen explained that prior IVUS trials have shown that statins slow progression or induce regression of coronary disease in proportion to the magnitude of LDL-C reduction. No other LDL-lowering therapy has shown regression in an IVUS trial, and the lowest LDL achieved in prior trials was approximately 60 mg/dL, with effects of lower levels remaining unknown.

PCSK9 inhibitors incrementally lower LDL when added to statins, allowing achievement of very low LDL levels; however, no data exist describing effects on atheroma progression or regression.

The GLAGOV trial enrolled 968 patients with angiographic coronary disease (mean age 59.8 years, 27.8% women, mean LDL-C 92.5 mg/dL) from 197 hospitals in North America, Europe, South America, Asia, Australia, and South Africa. All patients were taking statins at enrollment (60% high intensity, 40% moderate intensity).

Participants were randomized to receive monthly evolocumab (420 mg) or placebo by subcutaneous injection for 76 weeks in addition to statins. Of enrolled patients, 846 had evaluable imaging at follow-up.

The primary efficacy measure was nominal change in percent atheroma volume (PAV) from baseline to week 78, measured by IVUS. Secondary efficacy measures were nominal change in normalized total atheroma volume (TAV) and percentage of patients with plaque regression.

After 18 months, mean LDL-C levels were 93.0 mg/dL with placebo and 36.6 mg/dL with evolocumab, a difference of 56.5 mg/dL.

The primary efficacy end point, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab, a difference of −1.0% (95% CI −1.8 to −0.64, P<0.001).

The secondary efficacy end point, normalized TAV, decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab, a difference of −4.9 mm3 (95% CI −7.3 to −2.5, P<0.001).

Plaque regression in terms of PAV occurred in 64.3% of evolocumab patients vs 47.3% of placebo patients, a difference of 17.0% (95% CI 10.4−23.6, P<0.001). In terms of TAV, regression occurred in 61.5% of evolocumab patients vs 48.9% of those on placebo, a difference of 12.5% (95% CI 5.9−19.2, P<0.001).

Better Regression With Even Lower LDL Levels

In an exploratory subgroup analysis in patients with baseline LDL-C levels less than 70 mg/dL, those given evolocumab achieved a mean LDL-C level of 24 mg/dL (with the lowest level reached of 15 mg/dL). The evolocumab group also showed a larger regression of atheroma (−1.97% change in PAV), and 81% of patients had regression.

Nissen commented: "We have never seen levels of regression like this before—it is quite extraordinary."

He noted that as LDL was reduced from about 110 mg/dL to 20 mg/dL, "we see a continuous reduction in atheroma volume—with a linear relationship right down to the lowest LDL levels reached in this trial."

"We haven't gone this far down before, and we were perfectly prepared that there may be a leveling out of benefit at some threshold LDL level under 60 mg/dL, but we didn't see that. The benefit in terms of atheroma reduction continued to be greater right down to LDL levels as low as 20 mg/dL."

The study was not large enough to make any definitive statements about clinical events or safety, but Nissen noted that cardiovascular events were trending in the right direction (15.3% on placebo vs 12.2% on evolocumab), and adverse events looked reassuring, with no excess of myalgia, neurocognitive events, or new onset diabetes.

The study was sponsored by Amgen. Nissen reports consulting for many pharmaceutical companies and research grants from Abbvie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Novartis, Novo Nordisk, Medtronic, the Medicines Company, and Pfizer. Nicholls reports receiving research support from AstraZeneca, Cerenis, Amgen, Novartis, Eli Lilly, Anthera, LipoScience, Roche, Sanofi-Regeneron, and Resverlogix and receiving honoraria from or serving as a consultant for Amgen, AstraZeneca, Roche, Esperion, Eli Lilly, Abbott, Pfizer, Merck, Takeda, LipoScience, Omthera, Novo Nordisk, Sanofi-Regeneron, Atheronova, Anthera, CSL Behring, and Boehringer Ingelheim. Disclosures for the coauthors are listed in the article. Santos consults and receives research grants from Amgen.

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