Practice Update: Cardiology

AMERICAN HEART ASSOCIATION ANNUAL SCIENTIFIC SESSIONS 24

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.

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.

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.

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.

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

PRACTICEUPDATE CARDIOLOGY