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Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients - The GLAGOV Randomized Clinical Trial
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December 13, 2016
Key Points
QuestionDoes treatment with a PCSK9 inhibitor modify coronary atherosclerosis disease progression?
to our knowledge, no trials to date have explored whether LDL-C lowering with a PCSK9 inhibitor reduces the rate of progression of coronary atherosclerosis, and no data exist assessing whether achieving very low LDL-C levels via combination therapy results in incremental benefits in reducing disease progression compared with statins alone. The GLAGOV (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound) trial was designed to assess whether PCSK9 inhibition reduces progression of atherosclerosis as measured by IVUS.
FindingsIn this clinical trial in which 968 patients with coronary disease were treated with the PCSK9 inhibitor evolocumab or placebo monthly for 76 weeks and underwent serial intravascular ultrasound determination of coronary atheroma volume, lower low-density lipoprotein cholesterol levels were observed in the evolocumab group (36.6 vs 93.0 mg/dL), which also was associated with a reduction in percent atheroma volume for evolocumab (-0.95%) but not placebo (+0.05%) and a greater percentage of patients demonstrating plaque regression (64.3% vs 47.3%).
Meaning Addition of the PCSK9 inhibitor evolocumab to statin therapy produced greater low-density lipoprotein cholesterol lowering and atheroma regression.
Abstract
Importance Reducing levels of low-density lipoprotein cholesterol (LDL-C) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors produce incremental LDL-C lowering in statin-treated patients; however, the effects of these drugs on coronary atherosclerosis have not been evaluated.
Objective To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients.
Design, Setting, and ParticipantsThe GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment May 3, 2013, to January 12, 2015) conducted at 197 academic and community hospitals in North America, Europe, South America, Asia, Australia, and South Africa and enrolling 968 patients presenting for coronary angiography.
InterventionsParticipants with angiographic coronary disease were randomized to receive monthly evolocumab (420 mg) (n = 484) or placebo (n = 484) via subcutaneous injection for 76 weeks, in addition to statins.
Main Outcomes and Measures The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to week 78, measured by serial intravascular ultrasonography (IVUS) imaging. Secondary efficacy measures were nominal change in normalized total atheroma volume (TAV) and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated.
Results Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, -56.5 mg/dL [95% CI, -59.7 to -53.4]; P < .001). The primary efficacy parameter, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, -1.0% [95% CI, -1.8% to -0.64%]; P < .001). The secondary efficacy parameter, normalized TAV, decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab (difference, -4.9 mm3 [95% CI, -7.3 to -2.5]; P < .001). Evolocumab induced plaque regression in a greater percentage of patients than placebo (64.3% vs 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P < .001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P < .001 for TAV).
Conclusions and Relevance Among patients with angiographic coronary disease treated with statins, addition of evolocumab, compared with placebo, resulted in a greater decrease in PAV after 76 weeks of treatment. Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes.
Exploratory Clinical Events and Laboratory Adverse Events
Table 4 describes centrally adjudicated clinical events, clinical adverse events, laboratory abnormalities, and reasons for study discontinuation. Although the study was not powered to assess effects on cardiovascular events, exploratory analysis revealed numerically fewer adverse cardiovascular outcomes (12.2% vs 15.3%), nonfatal myocardial infarctions (2.1% vs 2.9%), and coronary revascularization procedures (10.3% vs 13.6%) in the evolocumab vs placebo groups. Administration of evolocumab was well tolerated, with no significant excess in rate of injection site reactions (0.4% vs 0%), myalgia (7.0% vs 5.8%), and neurocognitive events (1.4% vs 1.2%). The rates of laboratory abnormalities were low in both groups. Only 1 patient (0.2%) developed antievolocumab antibodies, and none had neutralizing antibodies detected. Hemoglobin A1c levels did not change in either treatment group.
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