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Dr Peter Libby discusses the
GLAGOV study
Peter Libby MD Dr Libby is Chief of Cardiovascular Medicine, Brigham and Women’s Hospital and Mallinckrodt
Professor of Medicine, Harvard Medical School in Boston, Massachusetts.
With the remarkable lipid lowering enabled by the
combination of statin and anti-PCSK9 antibodies,
wemay be wringing as much “milk out of the stone” as
we can by lessening lipid accumulation in the atheroma.
This consideration indicates that wemay be plumbing
the limits of clinically beneficial LDL lowering with
the remarkable therapies we have at hand today.
T
he introduction of antibodies that inhibit
proprotein convertase subtilisin kexin type 9
(PCSK9) inhibitors promises to revolutionise
the treatment of hypercholesterolaemia due to
elevations in low-density lipoprotein (LDL).
Numerous studies have shown the ability of
these new agents to lower LDL profoundly even
in patients well treated with statins. Preliminary
compilations of data from smaller studies provide
encouraging evidence regarding clinical benefit. Two
large-scale outcome trials in progress will inform
us within the next few years regarding the ability
of these monoclonal antibody therapies that target
PCSK9 to lower cardiovascular events in patients
at risk.
The Global Assessment of Plaque Regression With
a PCSK9 Antibody as Measured by Intravascular
Ultrasound (GLAGOV) study furnishes insight
into how treatment with anti-PCSK9 agents might
alter atherosclerotic plaques and the mechanisms
by which they might provide clinical benefit.
In this clinical trial, 968 patients with coronary
disease, almost all treated with statins, received
the anti-PCSK9 monoclonal antibody evolocumab
or placebo for 76 weeks and underwent serial
intravascular ultrasound (IVUS) study to quantify
coronary atheroma volume. The evolocumab-
treated group had reduced LDL concentrations
compared to those receiving placebo (36.6 vs
93.0mg/dL). Those receiving placebo slightly
increased the mean percent atheroma volume over
the approximately 18-month observation period
(+0.05%) while the evolocumab-treated group
showed a reduction in this measure of plaque
volume (−0.95%, P < 0.02 vs placebo).
GLAGOV shows that beyond statin treatment, the
additional LDL lowering altered plaque volume
about 1%, on the same order of reduction of statin
treatment versus placebo in prior ultrasound
studies. Statin treatment confers a disproportionate
reduction in clinical events (~20–45%) compared
to the small percentage improvement in mean
plaque volume (~1%). This finding indicates that
changes in qualitative features of plaques invisible
to ultrasound, not just quantity of plaque, may
influence the ability of LDL-lowering agents to
prevent cardiovascular events.
Experimental studies have shown that lipid lowering
can reduce plaque inflammation and reinforce
the plaque’s extracellular matrix, thus altering
functional characteristics of plaques related to their
liability to cause clinical complications. Indeed,
some of the clinical benefit of statins likely derives
from direct anti-inflammatory actions independent
of LDL lowering. In contrast to statins, this and
other studies show that anti-PCSK9 agents do
not lower the marker of inflammation, C-reactive
protein (CRP). We must await analysis of the
ongoing large-scale clinical endpoints studies
to ascertain whether the decrement in LDL
conferred by adding anti-PCSK9 agents to statins
will yield a further reduction in clinical events out
of proportion to the relatively modest decrease in
plaque volume, as in the case of statin treatment.
In GLAGOV, about half of the statin-treated
patients showed atheroma regression by the
ultrasound metrics evaluated. With the addition
of the biologic agent, about two-thirds of patients
showed regression over the 18-month study
duration. While longer treatment with the stringent
lipid-combination would likely produce further
regression of lesion volume, the authors point out
that shrinking atherosclerotic plaques by targeting
LDL alone may reach diminishing returns. With
the remarkable lipid lowering enabled by the
combination of statin and anti-PCSK9 antibodies,
we may be wringing as much “milk out of the stone”
as we can by lessening lipid accumulation in the
atheroma. This consideration indicates that we may
be plumbing the limits of clinically beneficial LDL
lowering with the remarkable therapies we have
at hand today. In an era of striving for “precision”
medicine, we should prepare to address a residual
burden of events in patients despite extreme
LDL lowering by targeting other potential drivers
of cardiovascular risk including inflammation or
other lipid risk factors such as triglyceride-rich
glycoproteins.
PRACTICEUPDATE CARDIOLOGY
AMERICAN HEART ASSOCIATION ANNUAL SCIENTIFIC SESSIONS
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