Characterization of Autosomal Dominant Hypercholesterolemia Caused by
            <i>PCSK9</i>
            Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody

Hopkins, Paul N.; Defesche, Joep C.; Fouchier, Sigrid W.; Bruckert, Éric; Luc, Gérald; Cariou, Bertrand; Sjouke, Barbara; Leren, Trond P.; Harada‐Shiba, Mariko; Mikami, Hiroshi; Rabès, Jean-Pierre; Carrié, Alain; Heyningen, Charles van; Carreau, Valérie; Farnier, Michel; Teoh, Yee Ping; Bourbon, Mafalda; Kawashiri, M-a; Nohara, Atsushi; Soran, Handrean; Marais, A. David; Tada, Hayato; Abifadel, Marianne; Boileau, Cathérine; Chanu, B.; Katsuda, Shoji; Kishimoto, Ichiro; Lambert, Gilles; Makino, Hisashi; Miyamoto, Yoshihiro; Pichelin, Matthieu; Yagi, Kunimasa; Yamagishi, Masakazu; Zaïr, Yassine; Mellis, Scott; Yancopouloš, George D.; Stahl, Neil; Mendoza, Johanna; Du, Yunling; Hamon, Sara; Krempf, Michel; Swergold, Gary D.

doi:10.1161/circgenetics.115.001129

Cited by 96 publications

(77 citation statements)

References 29 publications

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“…In patients adherent to treatment LDL‐C was reduced by 41% (2.2 mmol/L) mostly using the higher doses of PCSK‐9 inhibitor (74% at maximum licensed dose). PCSK‐9 therapy was effective producing a 70% LDL‐C reduction in a ‘homozygote’ patient actually a double heterozygote for LDLR and PCSK‐9 mutations . A <25% LDL‐C reduction was observed in 13% of patients.…”

Section: Discussionmentioning

confidence: 99%

“…A patient with a PCSK‐9 D129N mutation previously well‐controlled on statin and ezetimibe but with mild myalgia proved unresponsive to PCSK9 inhibitor monotherapy but did fully respond after re‐introduction of ezetimibe. The only previous trial of PCSK9 therapy in patients with mutations in PCSK9 added the therapy to baseline treatment with both statins and ezetimibe so data on primary response is lacking in this group …”

Section: Discussionmentioning

confidence: 99%

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Pro-protein subtilisin kexin-9 (PCSK9) inhibition in practice: lipid clinic experience in 2 contrasting UK centres

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pro-protein subtilisin kexin-9 (PCSK9) inhibition in practice: lipid clinic experience in 2 contrasting UK centres

et al. 2017

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“…It seems that general practitioners in the community tended to treat patients aiming for the normal range (LDL-C = 120 to 140 mg/dl), rather than to attain the targets determined by the guideline. The concept of “the lower, the better” in LDL-C level has been widely accepted, and such a situation will be achievable using new drugs, such as proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) inhibitor 13) . However, awareness itself to attain the current target should be the first step in the prevention of CAD.…”

Section: Discussionmentioning

confidence: 99%

Lipid Management in a Japanese Community:Attainment Rate of Target Set by the Japan Atherosclerosis Society Guidelines for the Prevention of Atherosclerotic Cardiovascular Diseases 2012

Tada

Kawashiri

Nohara

et al. 2017

JAT

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Aim: The Japan Atherosclerosis Society (JAS) guidelines for the prevention of atherosclerotic diseases 2012 (JAS2012) proposed lipid management targets; however, less data is available regarding the attainment rates of each target in community-based settings. Therefore, we assessed the attainment rates of lipid management targets among subjects who underwent Japanese specific health checkups.Methods: A total of 85,716 subjects (male = 29,282, 34.2%) aged 40–74 years who underwent specific health checkups from 2012 to 2014 in Kanazawa city, Japan, were included in this study. We evaluated the attainment rates of the lipid management targets according to the JAS2012 guideline and investigated the clinical characteristics of the subjects without achieving the targets.Results: The target for LDL cholesterol (LDL-C) was the least attained in all risk categories, 89, 72, 50, and 34% for category I, II, III, and secondary prevention, respectively, in 2014. In addition, these rates inversely correlated with the grade of risk categories (p-value for trends <0.001). Attainment rate of the LDL-C target in the suspected chronic kidney disease (CKD) group was significantly lower than in the groups with diabetes, stroke, or absolute risk in category III (49.2, 60.3, 63.5, 54.4%, respectively, p-value <0.001 for each). Moreover, the attainment rate of the LDL-C target was significantly lower in subjects that did not receive lipid-lowering therapy than in those who received it in the secondary prevention (27.7 and 40.6%, respectively, p-value <0.001).Conclusions: Lipid management is inadequate in community-based settings, particularly, in subjects with CKD and secondary prevention.

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“…The LSM percentage reduction in LDL‐C following 8 weeks of Q2W treatment with alirocumab plus atorvastatin was 73.2% . Another phase 2 study of alirocumab that enrolled 13 patients with 4 different PCSK9 gene GOF mutations showed a 62.5% LSM reduction from baseline in LDL‐C level at week 2 . When alirocumab was used as a monotherapy in the phase 3 ODYSSEY MONO trial (n = 103), hypercholesterolemic patients with a 10‐year risk for fatal CV events of ≥1% and <5% achieved an LSM reduction of LDL‐C level of 47.2% .…”

Section: Pcsk9 Inhibitorsmentioning

confidence: 99%

PCSK9 Inhibition With Monoclonal Antibodies: Modern Management of Hypercholesterolemia

Ito

Santos

2016

The Journal of Clinical Pharma

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Current guidelines for hypercholesterolemia treatment emphasize lifestyle modification and lipid‐modifying therapy to reduce the risk for cardiovascular disease. Statins are the primary class of agents used for the treatment of hypercholesterolemia. Although statins are effective for many patients, they fail to achieve optimal reduction in lipids for some patients, including those who have or are at high risk for cardiovascular disease. The PCSK9 gene was identified in the past decade as a potential therapeutic target for the management of patients with hypercholesterolemia. Pharmacologic interventions to decrease PCSK9 levels are in development, with the most promising approach using monoclonal antibodies that bind to PCSK9 in the plasma. Two monoclonal antibodies, alirocumab and evolocumab, have recently been approved for the treatment of hypercholesterolemia, and a third one, bococizumab, is in phase 3 clinical development. All 3 agents achieve significant reductions in levels of low‐density lipoprotein cholesterol, as well as reductions in non‐high‐density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). Long‐term outcome trials are under way to determine the sustained efficacy, safety, and tolerability of PCSK9 inhibitors and whether this novel class of agents decreases the risk for major cardiovascular events in patients on lipid‐modifying therapy. Available data suggest that PCSK9 inhibitors provide a robust reduction in atherogenic cholesterol levels with a good safety profile, especially for patients who fail to obtain an optimal clinical response to statin therapy, those who are statin intolerant or have contraindications to statin therapy, and those with familial hypercholesterolemia.

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Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody

Abstract: Supplemental Digital Content is available in the text.

Cited by 96 publications

References 29 publications

Pro-protein subtilisin kexin-9 (PCSK9) inhibition in practice: lipid clinic experience in 2 contrasting UK centres

Pro-protein subtilisin kexin-9 (PCSK9) inhibition in practice: lipid clinic experience in 2 contrasting UK centres

Lipid Management in a Japanese Community:Attainment Rate of Target Set by the Japan Atherosclerosis Society Guidelines for the Prevention of Atherosclerotic Cardiovascular Diseases 2012

PCSK9 Inhibition With Monoclonal Antibodies: Modern Management of Hypercholesterolemia

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