Guest Editorial: Commentary on the Findings of the GLAGOV Randomized Clinical Trial

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Evolocumab – a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) – significantly reduces low-density lipoprotein cholesterol levels. This agent has been tested in a series of clinical trials, one of which is discussed here: the GLAGOV study. Statintreated patients with coronary disease were treated with evolocumab or placebo with the result that patients in the evolocumab group low-density lipoprotein cholesterol (LDL-C) levels were significantly lower than the placebo group. Athersclerotic plaque regression was noticed in greater number of patients treated with evolocumab compared with placebo (64.3% versus 47.3%). While we await results from large outcome trials on PCSK9 inhibitors, the GLAGOV trial provides interesting findings of clinical advantages that may extend to LDL-C levels as low as 20 mg/dl.



Correspondence Details:Jakub Podolec MD, PhD, Department of Interventional Cardiology Jagiellonian University College of Medicine and the John Paul II Hospital, Pradnicka 80 Str., 31-202 Krakow, Poland. E:

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Atherosclerosis is the primary cause of coronary artery disease morbidity and mortality worldwide.1 Low-density lipoprotein cholesterol (LDL-C)- lowering therapies have already become one of the most important in the prevention of atherosclerosis complications.2 Evolocumab is a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) and thus significantly reduces levels of LDL-C, and has been tested in a series of clinical trials on a wide range of lipid disorders.3,4

The Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) study was a multicenter, randomized, double-blind, placebo-controlled clinical trial, which assessed the efficacy of the PCSK9 inhibitor evolocumab (Repatha®), measured by invasive intravascular ultrasound (IVUS).5 Patients aged ≥18 years with at least one non-significant coronary artery lesion with diameter stenosis >20 % were enrolled into the trial. All patients had to fulfill the following criteria:

  • Patients on stable dose of atorvastatin (20–80 mg daily) (NB: If the dose of atorvastatin was not stable at the time of screening, the patient was introduced in a 4-week lipid stabilization period, after which control lipidogram was performed).
  • LDL-C levels >80 mg/dl or 60–80 mg/dl in the presence of at least one of the major risk factors (myocardial infarction or hospitalization for unstable in recent 2 years, type 2 diabetes mellitus, extra-coronary atherosclerosis) or minor risk factors including age (men aged ≥50 years; women aged ≥55 years), hypertension (blood pressure ≥140/90 mmHg or current use of antihypertensive medications), low high-density lipoprotein (HDL) cholesterol (men: <40 mg/dl; women: <50 mg/dl), family history of premature coronary heart disease (first-degree male relative aged <55 years or female relative aged <65 years), high-sensitivity C-reactive protein ≥2 mg/l, or current cigarette smoking.

On screening, coronary angiography and IVUS imaging of coronary artery with non-significant lesion were performed. IVUS results were sent for further analysis to core laboratory (C5 Research, Cleveland Clinic).

Evolocumab 420 mg was given subcutaneously, using a disposable autoinjector, each month for 18 months. The control group received placebo in a blinded manner. Patients were controlled every 12 weeks for the presence of significant laboratory deviations.

The primary study endpoint was a nominal change in percent atheroma value (PAV) from baseline to week 78 of treatment determined by IVUS. Secondary endpoints included the assessment of nominal change in total atheroma volume (TAV) and the proportion of patients demonstrating any reduction of PAV or TAV from baseline. During the exploratory post-hoc analysis, comparison of the change in PAV and the percentage of patients undergoing regression of PAV in those with an LDL-C <70 mg/dl at baseline and locally weighted polynomial regression curve fitting was performed to examine the association between achieved LDL-C levels and disease progression.

From May 3, 2012 to January 12, 2015, a total of 2,628 patients were screened; 1,246 of these were enrolled. From this group, 276 were excluded based on protocol-specified criteria after lipid stabilization period or withdrawal of consent.


Overall, 968 patients were randomized (1:1) either to the intervention group receiving monthly evolocumab (n=484) or the control group receiving subcutaneous injections of placebo (n=484). At 76 weeks’ follow-up, 846 patients (87 %) had evaluable IVUS imaging. Both groups were well balanced according to age, sex, and coronary artery disease risk factors. In addition, baseline PAV and TAV did not differ significantly between groups.

Over 18 months, subcutaneous evolocumab 420 mg, used as an additional lipid-lowering therapy, achieved LDL-C levels averaging 36.6 mg/dl compared with 93 mg/dl in the statin-only group; led to significant regression in the mean change in PAV compared with the statin-only group; induced regression in a greater percentage of patients; and showed greater reduction in TAV with significant but not critical coronary artery narrowing. A post-hoc analysis showed an incremental benefit for combination therapy at LDL-C levels as low as 20 mg/dl.

After 76 weeks, mean LDL-C levels were significantly lower with evolocumab treatment, showing a 56.3 mg/dl decrease compared with a 0.2 mg/dl increase in the control group. The mean difference between groups was –56.5 mg/dl (95 % CI [–59.7 to –53.4]; p<0.001). The evolocumab-treated group had also decreased levels of apolipoprotein B, triglycerides, and lipoprotein(a). A higher increase in HDL-C levels was observed in the intervention group (3.3 mg/dl versus 0.8 mg/dl in placebo group; p<0.001).

Patients treated with evolocumab had a 0.95 % decrease in PAV, whereas patients treated with placebo had a 0.05 % increase in PAV, showing a difference of -1.0 % (95 % CI [-1.8 to -0.65) favoring evolocumab. In addition, decrease in TAV was greater among patients treated with evolocumab (-5.8 mm3 versus -0.9 mm3 in the control group); difference in TAV decrease was -4.9 mm3 (95 % CI [-7.3 to -2.5]; p<0.001) in favor of evolocumab. Plaque regression was induced in a greater percentage of patients receiving evolocumab than placebo (64.3 % versus 47.3 %; difference of 17.0 % [95 % CI [10.4–23.6]; p<0.001 for PAV and 61.5 % versus 48.9 %; difference of 12.5 % [95 % CI [5.9–19.2]; p<0.001 for TAV).

In 144 patients with baseline LDL-C levels of less than 70 mg/dL, evolocumab treatment, compared with placebo, was associated with greater change in PAV at week 78 of IVUS follow-up (-1.97 % versus -0.35 %; between-group difference, -1.62 % [95 % CI [-2.50 % to -0.74 %]; p<0.001). In this subgroup, the percentage of patients with regression of PAV for evolocumab compared with placebo was 81.2 % versus 48.0 % (between-group difference, 33.2 % [95 % CI [18.6 %–47.7 %]; p<0.001). A LOESS plot showed a linear relationship between achieved LDL-C level and PAV progression for LDL-C levels ranging from 110 mg/dL to as low as 20 mg/dl.5

Discussion and Conclusions

The GLAGOV trial revealed benefits of combination therapy in patients with baseline LDL-C below the lowest levels recommended by global guidelines (<70 mg/dl).

No safety issues, such as excess in new-onset diabetes, myalgia, or neurocognitive adverse effects, were identified at the mean LDL-C levels of 36.6 mg/dl achieved in the trial. However, it should be mentioned that the sample size of the trial was modest, providing limited power for safety assessments.

Over the years, LDL-C level has become one of the major factors in atherosclerosis progression. However, the question of how low lipid levels should be reduced to remains unknown.

Evidence has grown suggesting that optimal LDL-C levels for patients with coronary disease may be much lower than recommended. While we await results from large outcome trials on PCSK9 inhibitors, the GLAGOV trial provides interesting findings of clinical advantages that may extend to LDL-C levels as low as 20 mg/dl.

Further results from wide-scale randomized clinical trials, including the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial on long-term efficiency of evolocumab in secondary prevention of cardiovascular events,6 will hopefully address the most important questions that still remain unanswered.


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