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GLAGOV: Evolocumab added to statin therapy induces greater plaque regression
NEW ORLEANS — In the GLAGOV study, patients with CAD who had the PCSK9 inhibitor evolocumab added to their statin regimen experienced greater reductions in plaque metrics and LDL than those who had placebo added to their regimen.
“We have only ever had evidence for disease reduction with statins,” Steven E. Nissen, MD, MACC, chair of cardiovascular medicine at Cleveland Clinic and Cardiology Today Editorial Board member, said during a press conference at the American Heart Association Scientific Sessions. “No other LDL-lowering therapy has really shown these kinds of benefits, so we wanted to look at PCSK9 inhibitors to see if they also reduced disease progression.” In addition, he said, such an undertaking might provide insights on LDL levels lower than had been studied before.
Results with combination therapy
The researchers randomly assigned 968 patients with angiographic coronary disease (mean age, 60 years; 28% women; mean baseline LDL, 92.5 mg/dL) at 197 centers in Asia, Australia, Europe, North America, South America and South Africa to receive a once-monthly subcutaneous injection of evolocumab (Repatha, Amgen) 420 mg or placebo for 76 weeks. Nearly all of those enrolled were being treated with statin therapy. Patients had LDL levels > 80 mg/dL or, if they had one to three CV risk factors, LDL levels of 60 mg/dL to 80 mg/dL. At the end of follow-up, 846 patients had evaluable imaging.
The primary outcome was change in percent atheroma volume from baseline to 78 weeks as measured by IVUS. Secondary outcomes included change in total atheroma volume and percentage of each group who experienced plaque regression. The researchers also evaluated safety and tolerability metrics. The findings were simultaneously published in JAMA.
At the end of the study period, mean time-weighted LDL levels were lower in the evolocumab group than in the placebo group (36.6 mg/dL vs. 93 mg/dL; difference, –56.5 mg/dL; 95% CI, –59.7 to –53.4; P < .001), Nissen said.
Percent atheroma volume increased 0.05% in the placebo group, but declined 0.95% in the evolocumab group (difference, –1%; 95% CI, –1.8 to –0.64; P < .0001), according to the results.
Normalized total atheroma volume declined 0.9 mm3 in the placebo group and 5.8 mm3 in the evolocumab group (difference, –4.9 mm3; 95% CI, –7.3 to –2.5; P < .0001), Nissen said.
Plaque regression occurred more often in the evolocumab group than in the placebo group. Regression of percent atheroma volume was observed in 64.3% of the evolocumab group vs. 47.3% of the control group (difference, 17%; 95% CI, 10.4-23.6; P < .0001), while regression of total atheroma volume was observed in 61.5% of the evolocumab group vs. 48.9% of the control group (difference, 12.5%; 95% CI, 5.9-19.2; P < .001), according to the results.
Nissen and colleagues also conducted an exploratory subgroup analysis of patients who had baseline LDL < 70 mg/dL. In this cohort, the placebo group had a pre-dose mean LDL of 70.6 mg/dL and a post-dose mean LDL of 65.5 mg/dL, but the evolocumab group had a pre-dose mean LDL of 24 mg/dL and a post-dose mean LDL of 15 mg/dL, he said. In that subgroup, patients assigned evolocumab had a reduction in percent atheroma volume of 1.97% (P < .0001) and 81.2% had plaque regression, he said.
“We had never seen regression at those levels of magnitude,” Nissen said. “It was really quite extraordinary.” Reduction in LDL confers “a continuous reduction in disease progression; it’s very nearly a straight line, with no tailing-off effect of very, very low LDL,” he said.
Results were consistent across age, sex, HDL, diabetes and statin-intensity subgroups, according to the researchers.
The GLAGOV study was not powered for clinical endpoints, but clinical adverse events were numerically lower in the evolocumab group and there were no signals of excess new-onset diabetes, neurocognitive events or myalgia, Nissen said.
‘New era’ in lipid management
While the definitive word on effect of clinical outcomes will have to wait until clinical outcome trials are completed, “we think this is a signal that suggests that there may be benefits of really low LDL levels,” Nissen said.
“While we await the outcomes trials, GLAGOV is … the first intriguing evidence that clinical benefits may extend to LDL levels as low as 20 mg/dL,” Nissen said. “I thought there might be diminishing returns at lower levels. We didn’t see that.”
During a discussion of the findings, Raul D. Santos, MD, PhD, MSc, from Incor – University of Sao Paolo, Hospital Israelita Albert Einstein, Sao Paolo, Brazil, said while the GLAGOV study did not evaluate CV event reduction, it “confirms the role of LDL lowering, especially by increasing the number of LDL receptors on the liver. It suggests the start of a new era in lipid management.” – by Erik Swain
References:
Nissen SE, et al. LBCT.03 – Insights from New Therapeutic Trials for Lipids. Presented at: American Heart Association Scientific Sessions; Nov. 12-16, 2016; New Orleans.
Nicholls SJ, et al. JAMA. 2016;doi:10.1001/jama.2016.16951.
Disclosure: The study was funded by Amgen. Nissen reports receiving research support from AbbVie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion Therapeutics, Novo Nordisk, Orexigen, Pfizer, Takeda and The Medicines Company and consulting for a number of pharmaceutical companies without financial compensation; he reports that all honoraria, consultant fees or any other payments from any for-profit entity are paid directly to charity. Santos reports receiving research funding from Amgen.
Perspective
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The idea that further lowering of LDL relates to more plaque reduction is an important finding, and we need to wait to see whether that is going to benefit patients in the FOURIER and ODYSSEY OUTCOMES trials of two different PCSK9 inhibitors. What will be interesting to know is, does the reduction in the amount of plaque at lower levels of LDL, as they get down into the low 30s and 20s, have an impact on outcome? Or, alternatively, is there a plateau effect on outcome that doesn’t relate to the absolute anatomic change in the arterial wall? That’s an unanswered question. My thoughts are that we’re going to have a plateau effect on events, but that’s simply a hypothesis that the outcome trials are going to answer.