Safety of Very Low Low-Density Lipoprotein Cholesterol Levels With Alirocumab

Robinson, Jennifer G.; Rosenson, Robert S.; Farnier, Michel; Chaudhari, Umesh; Sasiela, William J.; Merlet, Laurence; Miller, Kathryn; Kastelein, John J.P.

doi:10.1016/j.jacc.2016.11.037

Cited by 180 publications

(139 citation statements)

References 25 publications

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“…Analyses from the ODYSSEY phase 3 clinical trial program reported a substantial proportion of patients having LDL‐C reductions to levels of <50 mg/dL10 and some to <25 mg/dL11 with the PCSK9 inhibitor alirocumab added, in the most part, to background statin therapy with or without other lipid‐lowering therapy. In addition, a continuous relationship between lower on‐treatment LDL‐C (including levels <50 mg/dL) and lower incidence of major adverse cardiovascular events (MACE) was observed 10.…”

Section: Introductionmentioning

confidence: 99%

Lower On‐Treatment Low‐Density Lipoprotein Cholesterol and Major Adverse Cardiovascular Events in Women and Men: Pooled Analysis of 10 ODYSSEY Phase 3 Alirocumab Trials

Vallejo‐Vaz

Ginsberg

Davidson

et al. 2018

JAHA

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BackgroundIn statin trials, men and women derived similar relative risk reductions in cardiovascular events per 39 mg/dL low‐density lipoprotein cholesterol (LDL‐C) reduction. We explored whether lower LDL‐C levels and greater LDL‐C percentage reductions than those achieved with statins are associated with reduced major adverse cardiovascular event (MACE) rates in women as well as men.Methods and ResultsData pooled from 10 phase 3 ODYSSEY randomized trials (n=4983) comparing alirocumab with control (placebo/ezetimibe) were assessed for association between 39 mg/dL lower on‐treatment LDL‐C and percentage LDL‐C change from baseline, and MACE risk by sex, using multivariable Cox regression. Mean baseline LDL‐C was 135 mg/dL (women) and 121 mg/dL (men). Average on‐treatment LDL‐C levels with alirocumab, ezetimibe, and placebo were 71, 114, and 134 mg/dL, respectively, in women (n=1882) and 52, 93, and 122 mg/dL, respectively, in men (n=3090). Overall, 36.5% and 58.7% of women and men, respectively, achieved on‐treatment LDL‐C <50 mg/dL. Each 39 mg/dL lower LDL‐C was associated with a 33% and 22% lower risk of MACE in women (P=0.0209) and men (P=0.0307), respectively, with no significant between‐sex difference (P for heterogeneity=0.4597). Results were similar when analyzed per 50% LDL‐C reduction, 24% (P=0.1094) and 29% (P=0.0125) lower MACE risk in women and men, respectively (P for heterogeneity=0.7499). Alirocumab was generally well tolerated in both sexes.ConclusionsThe present analysis reinforces the notion that both sexes derive a similar cardiovascular benefit from LDL‐C lowering. Although women had slightly higher on‐treatment LDL‐C than men, both sexes showed a similar lower MACE risk with lower LDL‐C.

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Section: Introductionmentioning

confidence: 99%

Lower On‐Treatment Low‐Density Lipoprotein Cholesterol and Major Adverse Cardiovascular Events in Women and Men: Pooled Analysis of 10 ODYSSEY Phase 3 Alirocumab Trials

Vallejo‐Vaz

Ginsberg

Davidson

et al. 2018

JAHA

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confidence: 84%

“…The apparent lack of association between the LDL-Cholesterol <25 and <15 mg/dl and the risk of neurocognitive disorders can be due to the scarce power of these analyses. Indeed, the sample size of the groups exposed to those targets [1] can demonstrate with sufficient statistical power (≥80%), only very large hypothetical increases in risk of neurocognitive events (RRs ≥2.6 and ≥3.4 respectively).…”

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confidence: 99%

PCSK9-AB and risk of neurocognitive events – comments to Robinson’s meta-analysis

Battaggia¹,

Scalisi²,

Schivalocchi³

et al. 2017

J Integr Cardiol

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A pooled analysis [1] does not found worse safety profiles in patients reaching very low values of LDL-Cholesterol (<25 and <15 mg/ dl) compared to higher LDL-Cholesterol levels. Authors concluded that aggressive alirocumab therapy seems generally well tolerated. We raise some methodological questions.First, Authors' analyses used propensity scores from regression models lacking in predictors of safety endpoints, while covariates must be associated to both outcome and exposition: associations with exposition only affect the analytical precision and do not adjust for possible confounders [2].Second, limiting the evaluation to alirocumab therapies and focusing to very-low LDL-Cholesterol values subgroups reduces the power of comparisons and increases the risk of false negatives. The apparent lack of association between the LDL-Cholesterol <25 and <15 mg/dl and the risk of neurocognitive disorders can be due to the scarce power of these analyses. Indeed, the sample size of the groups exposed to those targets [1] can demonstrate with sufficient statistical power (≥80%), only very large hypothetical increases in risk of neurocognitive events (RRs ≥2.6 and ≥3.4 respectively).

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“…Алирокумаб приводил к стой-кому снижению уровня ХС-ЛНП на 61% от исходных значений. Ретроспективный анализ показал сущест-венное снижение риска ССО на 48% среди пациен-тов, получавших алирокумаб (р=0,02) [52]. Возмож-ность применения алирокумаба при остром коронар-ном синдроме, а также влияние этого препарата на течение и прогноз хронических атеросклеротиче-ских ССЗ изучались в крупном рандомизированном исследовании ODYSSEY OUTCOMES [53] с участием почти 19000 пациентов с недавним (менее одного года) острым коронарным синдромом.…”

Section: препараты на основе антисмысловых олигонуклеотидов (асо)unclassified

“…Способность ингибиторов PCSK9 снижать уровни ХС ЛНП до крайне низких значений подняла вопросы безопасности такого лечения. Для ответа на них Robinson J, et al изучили суммарную частоту побочных эффектов в 14 иссле-дованиях программы ODYSSEY [52]. Авторы про-анализировали данные 3340 пациентов, получавших алирокумаб, и 1894 пациентов групп сравнения (у которых применяли плацебо или эзетимиб).…”

Section: препараты на основе антисмысловых олигонуклеотидов (асо)unclassified

Antisense Oligonucleotides and Therapeutical Monoclonal Antibodies as a Basement for Novel Biological Lipidlowering Drugs

2018

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Development of innovational biotechnological medications based on humanized or completely human monoclonal antibodies or antisense oligonucleotides has opened a novel epoque in lipid disorders treatment. High efficacy of such biological drugs influencing the main chains of lipid metabolism (apoprotein B100, apoprotein (a), apoprotein CIII, proprotein-convertase subtilisin-kexin type 9, antipoetin like protein 3) does open a perspective for correction of severe and statin-resistant forms of dyslipidemias, with a possibility to achieve almost complete remission of the disease. However, the evidence of safety of antisense oligonucleotides drugs demands for broader investigation. Such drugs might be used in patients with orphan diseases or serious lipid disorders, not having alternative treatment. Vice versa, the drugs based on the human monoclonal antibodies thank to evidence are started to be in clinical use at the moment.

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Safety of Very Low Low-Density Lipoprotein Cholesterol Levels With Alirocumab

Cited by 180 publications

References 25 publications

Lower On‐Treatment Low‐Density Lipoprotein Cholesterol and Major Adverse Cardiovascular Events in Women and Men: Pooled Analysis of 10 ODYSSEY Phase 3 Alirocumab Trials

Lower On‐Treatment Low‐Density Lipoprotein Cholesterol and Major Adverse Cardiovascular Events in Women and Men: Pooled Analysis of 10 ODYSSEY Phase 3 Alirocumab Trials

PCSK9-AB and risk of neurocognitive events – comments to Robinson’s meta-analysis

Antisense Oligonucleotides and Therapeutical Monoclonal Antibodies as a Basement for Novel Biological Lipidlowering Drugs

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