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• W2891806873 abstract "HomeCirculationVol. 138, No. 12Letter by Koh Regarding Article, “PCSK9 Variants, Low-Density Lipoprotein Cholesterol, and Neurocognitive Impairment: Reasons for Geographic and Racial Differences in Stroke Study (REGARDS)” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Koh Regarding Article, “PCSK9 Variants, Low-Density Lipoprotein Cholesterol, and Neurocognitive Impairment: Reasons for Geographic and Racial Differences in Stroke Study (REGARDS)” Kwang Kon Koh, MD, PhD Kwang Kon KohKwang Kon Koh Department of Cardiovascular Medicine, Heart Center, Gachon University, Gil Medical Center, Incheon, Korea. Gachon Cardiovascular Research Institute, Incheon, Korea. Search for more papers by this author Originally published17 Sep 2018https://doi.org/10.1161/CIRCULATIONAHA.118.035495Circulation. 2018;138:1283–1284To the Editor:Mefford et al1 report that that lifelong exposure to low PCSK9 (proprotein convertase subtilisin/kexin type-9) levels and cumulative exposure to lower levels of low-density lipoprotein cholesterol are not associated with neurocognitive effects in blacks.Recent studies showed that low-density lipoprotein (LDL)-cholesterol levels <25 mg/dL or <15 mg/dL on a PCSK9 inhibitor, alirocumab, were not associated with an increase in overall treatment-emergent adverse event rates or neurocognitive events, although cataract incidence increased 3 times in the group achieving LDL-cholesterol levels <25 mg/dL.2 However, the follow-up period is not enough to be safe. Although evolocumab was not correlated with reduced cognitive function over a median of 19 months,3 more prolonged exposure to extremely low LDL-cholesterol levels could cause neurocognitive dysfunction, cataract, and new-onset diabetes mellitus, because it would impair cellular function, although these studies reported no incidence of diabetes mellitus.Statins are important for preventing adverse cardiovascular events in patients with both a high risk and a low risk of vascular disease by reducing the levels of LDL-cholesterol. However, statins dose-dependently increase adverse effects and increase the risk of type 2 diabetes mellitus.4 This was previously hypothesized to be attributable to off-target effects, but recent studies have demonstrated that it was attributable to on-target effects.4 Like statins, PCSK9 inhibitors may increase adverse effects and increase the risk of type 2 diabetes mellitus. In the mendelian randomization study, data from cohort studies, randomized controlled trials, case control studies, and genetic consortia were used to estimate associations of PCSK9 genetic variants with LDL-cholesterol, fasting blood glucose, hemoglobin A1c, fasting insulin, etc, and risk of type 2 diabetes mellitus by using a standardized analysis plan, meta-analyses, and weighted gene-centric scores. Combined analyses of 4 independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL-cholesterol showed associations with increased fasting glucose (0.09 mmol/L; 95% CI, 0.02–0.15), bodyweight (1.03 kg; 0.24–1.82), waist-to-hip ratio (0.006; 0.003–0.010), and an odds ratio for type 2 diabetes mellitus of 1.29 (1.11–1.50). PCSK9 variants associated with lower LDL-cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes mellitus.5 In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.4,5Sources of FundingThis work was supported by a grant of the Korean Society of CardioMetabolic Syndrome.DisclosuresNone.Footnoteshttps://www.ahajournals.org/journal/circReferences1. Mefford MT, Rosenson RS, Cushman M, Farkouh ME, McClure LA, Wadley VG, Irvin MR, Bittner V, Safford MM, Somaratne R, Monda KL, Muntner P, Levitan EB. PCSK9 variants, low-density lipoprotein cholesterol, and neurocognitive impairment: Reasons for Geographic and Racial Differences in Stroke Study (REGARDS).Circulation. 2018; 137:1260–1269. doi: 10.1161/CIRCULATIONAHA.117.029785LinkGoogle Scholar2. Robinson JG, Rosenson RS, Farnier M, Chaudhari U, Sasiela WJ, Merlet L, Miller K, Kastelein JJ. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: pooled data from randomized trials.J Am Coll Cardiol. 2017; 69:471–482. doi: 10.1016/j.jacc.2016.11.037CrossrefMedlineGoogle Scholar3. Giugliano RP, Mach F, Zavitz K, Kurtz C, Im K, Kanevsky E, Schneider J, Wang H, Keech A, Pedersen TR, Sabatine MS, Sever PS, Robinson JG, Honarpour N, Wasserman SM, Ott BR; EBBINGHAUS Investigators. Cognitive function in a randomized trial of evolocumab.N Engl J Med. 2017; 377:633–643. doi: 10.1056/NEJMoa1701131CrossrefMedlineGoogle Scholar4. Cho KI, Sakuma I, Sohn IS, Hayashi T, Shimada K, Koh KK. Best treatment strategies with statins to maximize the cardiometabolic benefits.Circ J. 2018; 82:937–943. doi: 10.1253/circj.CJ-17-1445CrossrefMedlineGoogle Scholar5. Schmidt AF, Swerdlow DI, Holmes MV, Patel RS, Fairhurst-Hunter Z, Lyall DM, Hartwig FP, Horta BL, Hyppönen E, Power C, Moldovan M, van Iperen E, Hovingh GK, Demuth I, Norman K, Steinhagen-Thiessen E, Demuth J, Bertram L, Liu T, Coassin S, Willeit J, Kiechl S, Willeit K, Mason D, Wright J, Morris R, Wanamethee G, Whincup P, Ben-Shlomo Y, McLachlan S, Price JF, Kivimaki M, Welch C, Sanchez-Galvez A, Marques-Vidal P, Nicolaides A, Panayiotou AG, Onland-Moret NC, van der Schouw YT, Matullo G, Fiorito G, Guarrera S, Sacerdote C, Wareham NJ, Langenberg C, Scott R, Luan J, Bobak M, Malyutina S, Pająk A, Kubinova R, Tamosiunas A, Pikhart H, Husemoen LL, Grarup N, Pedersen O, Hansen T, Linneberg A, Simonsen KS, Cooper J, Humphries SE, Brilliant M, Kitchner T, Hakonarson H, Carrell DS, McCarty CA, Kirchner HL, Larson EB, Crosslin DR, de Andrade M, Roden DM, Denny JC, Carty C, Hancock S, Attia J, Holliday E, O’Donnell M, Yusuf S, Chong M, Pare G, van der Harst P, Said MA, Eppinga RN, Verweij N, Snieder H, Christen T, Mook-Kanamori DO, Gustafsson S, Lind L, Ingelsson E, Pazoki R, Franco O, Hofman A, Uitterlinden A, Dehghan A, Teumer A, Baumeister S, Dörr M, Lerch MM, Völker U, Völzke H, Ward J, Pell JP, Smith DJ, Meade T, Maitland-van der Zee AH, Baranova EV, Young R, Ford I, Campbell A, Padmanabhan S, Bots ML, Grobbee DE, Froguel P, Thuillier D, Balkau B, Bonnefond A, Cariou B, Smart M, Bao Y, Kumari M, Mahajan A, Ridker PM, Chasman DI, Reiner AP, Lange LA, Ritchie MD, Asselbergs FW, Casas JP, Keating BJ, Preiss D, Hingorani AD, Sattar N; LifeLines Cohort study group; UCLEB consortium. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study.Lancet Diabetes Endocrinol. 2017; 5:97–105. doi: 10.1016/S2213-8587(16)30396-5CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails September 18, 2018Vol 138, Issue 12 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.035495PMID: 30354438 Originally publishedSeptember 17, 2018 PDF download Advertisement" @default.
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