Clinical Impact of PCSK9 Inhibitor on Stabilization and Regression of Lipid-Rich Coronary Plaques

Does Treatment With PCSK9 Inhibitors Wring Lipid out of Atheromatous Plaques?

Regression of atherosclerosis has proven a difficult challenge. Quantitative angiographic studies with statins showed very modest reductions in stenosis, on the order of the few red cell diameters.¹ Intravascular ultrasound imaging studies show that intense statin therapy could actually decrease the volume of atheromata. But, again, the shrinkage of plaques achieved by statin treatment proved rather minimal, on the order of a few percent.² In contrast to these perhaps disappointing changes in luminal caliber or atheroma volume, statin treatment produced reductions in cardiovascular events of much greater magnitude. This apparent paradox suggests that lipid lowering, particularly by statins, could change qualitative aspects of plaques that would render them less likely to cause thrombotic complications. This concept, denoted “plaque stabilization,” might accrue because of a decrease in the lipid content and accumulation of inflammatory cells as well as relative increases in the fibrous content, which would render plaques less likely to rupture and cause a myocardial infarction or other thrombotic event.³

We have now entered a new era when we can lower LDL to a greater extent than achievable with statin monotherapy or even a combination of statin plus ezetimibe. The anti-PCSK9 antibodies, and RNA therapeutics on the horizon, permit reductions of LDL into extremely low concentrations. Analysis of large-scale clinical trials with the antibodies that neutralize PCSK9 have shown progressive reductions in events as lower LDL levels are achieved.^4,5

Intravascular imaging studies have been useful in trying to understand the pathophysiological basis of plaque “stabilization.” A landmark trial, GLAGOV, demonstrated greater reductions in atheroma volume with evolocumab than with statin alone.⁶ Although intravascular ultrasound is very well validated for gauging plaque volume, it is much less able to assess the qualitative aspects of plaque structure, save for calcification, which can be studied indirectly by acoustic shadowing.

Ota and colleagues have combined intravascular ultrasound with near-infrared spectroscopy in a new intravascular study of the effects of PCSK9 inhibitors on plaque structure.⁷ The newer infrared technique provides information that may relate to the lipid content of plaque. The investigators not only confirmed the findings of GLAGOV but also provided evidence that the near-infrared spectroscopic signal, interpreted as indicating lipid content, decreased to a greater extent in patients treated with statin with PCSK9 inhibitors versus those not receiving this class of medication. This study thus gives us a new data point in understanding the mechanisms by which LDL lowering changes the qualitative characters of plaques. It thus may help explain the disparity between the minimal changes in plaque volume or degree of stenosis and the much more impressive reduction in clinical events achieved by LDL lowering.

Limitations of this study include its small size (21 and 32 patients, with follow-up in each group) and the lack of a randomized design for allocation of therapies. This design could lead to confounding by indication. The design also inherently led to imbalances in the baseline characteristics, as allocation to the PCSK9 inhibitor group was based on higher estimated risk compared with the control group. There was a substantial missing data issue due to drop out of participants. A general problem with the near-infrared method is lack of rigorous chemical characterization of the generation of the signal. Although the title of the article claims "stabilization," the study did not directly assess plaque stability.

We are fortunate to have in hand today tools that allow us mastery over LDL, an undisputed causal risk factor for atherosclerosis. Yet, even in those who achieve very low levels of LDL due to these novel therapies, the residual burden of events remains unacceptable. Further reduction in LDL will yield diminishing returns. Therefore, we must seek other aspects of dyslipidemia and other risk factors to continue progress in the prevention of atherosclerotic events. Promising targets include reductions in triglyceride-rich lipoproteins and inflammation and reaping the benefits of new antidiabetic therapies such as the GLP-1 receptor agonists and the SGLT2 inhibitors, agents with a cardiovascular protection that appears out of proportion to the degree of improvement in glycemic control.

References

1. Jukema JW, Bruschke AV, van Boven AJ, et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation. 1995;91(10):2528-2540. https://www.ahajournals.org/doi/10.1161/01.cir.91.10.2528
2. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291(9):1071-1080. https://jamanetwork.com/journals/jama/fullarticle/198311
3. Libby P, Aikawa M. Stabilization of atherosclerotic plaques: new mechanisms and clinical targets. Nat Med. 2002;8(11):1257-1262. https://www.nature.com/articles/nm1102-1257
4. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. https://www.nejm.org/doi/10.1056/NEJMoa1615664
5. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097-2107. https://www.nejm.org/doi/10.1056/NEJMoa1801174
6. Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA. 2016;316(22):2373-2384. https://jamanetwork.com/journals/jama/fullarticle/2584184
7. Ota H, Omori H, Kawasaki M, et al. Clinical impact of PCSK9 inhibitor on stabilization and regression of lipid-rich coronary plaques: a near-infrared spectroscopy study Eur Heart J Cardiovasc Imaging. 2021 Feb 26. Doi: 10.1093/ehjci/jeab034/6151204. Online ahead of print. https://academic.oup.com/ehjcimaging/advance-article/doi/10.1093/ehjci/jeab034/6151204