Letter by Koh Regarding Article, "Pleiotropic Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors?"

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HomeCirculationVol. 135, No. 17Letter by Koh Regarding Article, “Pleiotropic Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors?” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Koh Regarding Article, “Pleiotropic Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors?” Kwang Kon Koh, MD, PhD Kwang Kon KohKwang Kon Koh From Department of Cardiovascular Medicine, Heart Center, Gachon University Gil Medical Center; and Gachon Cardiovascular Research Institute, Incheon, Korea. Search for more papers by this author Originally published25 Apr 2017https://doi.org/10.1161/CIRCULATIONAHA.116.026821Circulation. 2017;135:e1006–e1007To the Editor:In her recent article, Bittner discussed pleiotropic effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.1 PCSK9 is a serine protease that is secreted by the liver, binds to the low-density lipoprotein (LDL) receptor, and directs the LDL receptor toward lysosomal degradation. PCSK9 inhibitors achieve LDL-cholesterol (LDL-C) reductions of 45% to 60% and similarly LDL particle number, small and large LDL particles, and apolipoprotein B levels. The impact of PCSK9 inhibition is not limited to reduction in LDL-C but also affects other aspects of lipoprotein metabolism, inflammation, thrombosis, and immune function. PCSK9 inhibitors lower lipoprotein (a) by as much as 30% and variably reduce triglyceride-rich lipoproteins possibly through enhanced clearance by LDL receptors and very LDL (VLDL) receptors or by lowering production of triglyceride-rich lipoproteins. Thus, PCSK9 antibodies lower LDL-C and other atherogenic lipoproteins and seem to favorably affect the complex inflammatory and thrombotic mechanisms related to atherosclerosis progression and acute events. Therefore, broad effects of PCSK9 inhibitors on multiple physiological systems come with concerns about the potential for unintended effects.1On the other hand, subjects with genetic variants in PCSK9 or HMGCR with reduced LDL levels had similar decreases in cardiovascular disease (CVD) risk per unit decrease in LDL-C.2,3 In subjects with preexisting glucose intolerance, variants in both genes were associated with independent and additive effects to increase risk of diabetes mellitus (also associated with LDL lowering albeit with smaller effect size than CVD risk).2 PCSK9 inhibitors and statins use distinct mechanisms to lower LDL-C, the common downstream effect that is likely related to both protection against CVD and promotion of diabetes mellitus. Together, these data strongly support large clinical outcome studies to determine whether a further increase in diabetes mellitus occurs with statin therapy.These data provide insights into the potential adverse effects of LDL-C-lowering therapy. What should we target, CVD risk or diabetes mellitus? Because new-onset diabetes mellitus adds substantially to CVD risk, a dilemma exists with combination therapy of high-potency statins combined with PCSK9 inhibitors. Also, we should think about cost-effectiveness. PCSK9 inhibitors are expensive and would be unnecessary except in patients with a CVD event or familial hypercholesterolemia+inadequate lowering of LDL-C with statins with or without stain intolerance. Statins are important, but we should also endeavor to control residual risk because reduction of LDL-C prevents <50% of CVD events.We have proposed statins-based combined therapy to balance cardiometabolic benefits and risks of statins. Statins-based combined therapy would simultaneously prevent new-onset diabetes mellitus and improve cardiovascular outcome because of the beneficial effects of renin-angiotensin system or ezetimibe on insulin resistance and endothelial dysfunction.4,5 In this regard, combined therapy demonstrates additive/synergistic effects on endothelial dysfunction and insulin resistance in addition to lowering LDL-C levels and blood pressure when compared with either monotherapy in patients. This finding is mediated by both distinct and interrelated mechanisms.4,5Kwang Kon Koh, MD, PhDAcknowledgmentsI deeply appreciate Dr Robert H. Eckel, Division of Endocrinology, Metabolism and Diabetes, University of Colorado, Denver, for his comment.DisclosuresNone.FootnotesCirculation is available at http://circ.ahajournals.org.