Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol

Ghosh, Moumita; Gälman, Cecilia; Rudling, Mats; Angelin, Bo

doi:10.1194/jlr.m055780

Cited by 79 publications

(51 citation statements)

References 33 publications

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“…In addition, the present study showed that patients with high plasma PCSK9 concentration were more likely to be female, which was consistent with previous studies [37,38]. The reason for this phenomenon may be that plasma PCSK9 levels are influenced by hormones such as estrogen [39]. Besides, we found that low PCSK9 levels were associated with the feature of smoking and drinking was inconsistent with other studies [40,41], which may need to investigate further in a large sample study.…”

Section: Discussionsupporting

confidence: 78%

Association of circulating PCSK9 concentration with cardiovascular metabolic markers and outcomes in stable coronary artery disease patients with or without diabetes: a prospective, observational cohort study

Jia

Liu

Jin

et al. 2020

Cardiovasc Diabetol

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Background Whether plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels is a predictor for cardiovascular outcomes has currently been controversial. No data is currently available regarding the relation of PCSK9 to cardiovascular metabolic markers (CVMMs) and major adverse cardiovascular events (MACEs) in stable coronary artery disease (CAD) patients with diabetes or without diabetes. Methods A total 1225 untreated patients with stable CAD were consecutively enrolled and their baseline plasma PCSK9 levels were determined by ELISA. Patients were divided into high and low PCSK9 groups according to PCSK9 median. All patients followed up for the occurrence of MACEs and received standard therapy after admission. The associations of PCSK9 with CVMMs and MACEs were evaluated. Results PCSK9 levels were positively correlated with multiple CVMMs including total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol and hemoglobin A1c at baseline (all p < 0.05). During a median follow-up of 3.3 years, 103 (8.4%) events occurred. PCSK9 levels were higher in patients with events compared to those without (p < 0.05). The Kaplan–Meier analysis displayed that patients in high PCSK9 group had lower event-free survival than that in low group (p < 0.05). Multivariable Cox regression analysis revealed that PCSK9 levels were independently associated with MACEs in diabetic patients (adjusted hazard ratio [HR]: 1.361, 95% confidence interval [CI]: 1.037–1.785, p < 0.05). When added the combination of PCSK9 levels and diabetic status to stratifying factors, patients in high PCSK9 group appeared to have extremely high risk of subsequent MACEs with diabetes (adjusted HR: 5.233, 95% CI: 2.546–10.757, p < 0.01). Conclusions The present study firstly showed that elevated PCSK9 levels were related to multiple CVMMs and MACEs in stable CAD with diabetes, suggesting that plasma PCSK9 measurement could help to identify diabetic patients with CAD at higher cardiovascular risk. More studies may be needed to confirm our findings.

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Section: Discussionsupporting

confidence: 78%

Association of circulating PCSK9 concentration with cardiovascular metabolic markers and outcomes in stable coronary artery disease patients with or without diabetes: a prospective, observational cohort study

Jia

Liu

Jin

et al. 2020

Cardiovasc Diabetol

View full text Add to dashboard Cite

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“…Prior studies have also shown PCSK9 levels to be elevated in females vs males, in both adults and children. 14,32,34,35 Furthermore, some of these studies found associations between PCSK9 and BMI that were either stronger or only present in females. 14 Interestingly, mice also appear to manifest a sex-dependent association between PCSK9 and body weight, although in this case, the association may be more prominent in males: leptin treatment of obese mice produced similar weight loss in males and females, which was associated with a 90% decrease in plasma PCSK9 in males, but no change in plasma PCSK9 in females.…”

Section: Discussionmentioning

confidence: 99%

Obesity and type 2 diabetes are associated with elevated PCSK9 levels in young women

et al. 2017

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Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of low-density lipoprotein (LDL) cholesterol and cardiovascular disease (CVD) risk, and is an emerging therapeutic target. Objective We compared serum PCSK9 levels in young adults, with and without type 2 diabetes. Subjects and Methods Cross-sectional analysis was conducted in a cohort, aged 15 to 26 years, in Cincinnati, OH, from 2005 to 2010. Serum PCSK9 levels were measured in 94 youth with type 2 diabetes, 93 obese control subjects, and 99 lean control subjects. Correlative analyses were conducted to determine significant covariates of PCSK9 by group and sex, and multivariate linear regression models were used to study the independent determinants of PCSK9. Results In females, PCSK9 levels were significantly increased in the obese and type 2 diabetes subjects relative to the lean controls (P < 0.01). Moreover, PCSK9 was positively correlated with multiple metabolic parameters in females: body mass index (BMI), systolic blood pressure (SBP), fasting glucose, fasting insulin, and C-reactive protein (CRP) levels (P≤0.02). In males, PCSK9 levels were decreased overall compared to females (P=0.03), and did not differ between the lean, obese, or type 2 diabetes groups. Conclusions Obesity and type 2 diabetes were associated with significantly higher levels of PCSK9 in young women, but not in young men. These data suggest that sex could modify the effects of obesity and diabetes on PCSK9 in young adults.

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“…A significant increase of approximately 30% in E max between the 5th and 95th percentiles of age (37 and 75 years, respectively) was observed, again consistent with previously published findings that show older patients derive more benefit from lipid-lowering therapies [ 45 ]. The relationship of age and sex with E max values, regardless of body weight, can be also partly explained by the commonly held view that physiological changes in hormone levels, such as loss of endogenous estrogen after menopause for women, influence circulating PCSK9 levels [ 46 ]. Furthermore, results of a recent quantitative systems pharmacology modeling study led the authors to hypothesize that the difference in cholesterol metabolism observed between sexes may be explained by estrogen regulation of a potentially less functional form of PCSK9 (form X), with differing efficacy of LDL-R degradation explaining the variability of response between patients [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic/Pharmacodynamic Analysis of Alirocumab in Healthy Volunteers or Hypercholesterolemic Subjects Using an Indirect Response Model to Predict Low-Density Lipoprotein Cholesterol Lowering: Support for a Biologics License Application Submission: Part II

et al. 2018

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Background Alirocumab, a human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly lowers low-density lipoprotein cholesterol levels. Objective This analysis aimed to develop and qualify a population pharmacokinetic/pharmacodynamic model for alirocumab based on pooled data obtained from 13 phase I/II/III clinical trials. Methods From a dataset of 2799 individuals (14,346 lowdensity lipoprotein-cholesterol values), individual pharmacokinetic parameters from the population pharmacokinetic model presented in Part I of this series were used to estimate alirocumab concentrations. As a second step, we then developed the current population pharmacokinetic/ pharmacodynamic model using an indirect response model with a Hill coefficient, parameterized with increasing lowdensity lipoprotein cholesterol elimination, to relate alirocumab concentrations to low-density lipoprotein cholesterol values. Results The population pharmacokinetic/pharmacodynamic model allowed the characterization of the pharmacokinetic/pharmacodynamic properties of alirocumab in the target population and estimation of individual lowdensity lipoprotein cholesterol levels and derived pharmacodynamic parameters (the maximum decrease in lowdensity lipoprotein cholesterol values from baseline and the difference between baseline low-density lipoprotein cholesterol and the pre-dose value before the next alirocumab dose). Significant parameter-covariate relationships were retained in the model, with a total of ten covariates (sex, age, weight, free baseline PCSK9, total time-varying PCSK9, concomitant statin administration, total baseline PCSK9, co-administration of high-dose statins, disease status) included in the final population pharmacokinetic/pharmacodynamic model to explain betweensubject variability. Nevertheless, the high number of covariates included in the model did not have a clinically meaningful impact on model-derived pharmacodynamic parameters. Conclusions This model successfully allowed the characterization of the population pharmacokinetic/pharmacodynamic properties of alirocumab in its target population and the estimation of individual low-density lipoprotein cholesterol levels. Key PointsThe population pharmacokinetic/pharmacodynamic model of alirocumab successfully described the relationship between alirocumab concentrations and low-density lipoprotein cholesterol (LDL-C) levels in the target population of 2799 healthy volunteers or patients from 13 phase I/II/III clinical studies.The population pharmacokinetic/pharmacodynamic model allowed the estimation of individual LDL-C levels and derived pharmacodynamic parameters (the maximum decrease in LDL-C values from baseline and the difference between baseline LDL-C and the pre-dose value before the next alirocumab dose).Ten covariates were included in the final model, all exhibiting moderate to strong effects on the model parameters; however, although some covariates were associated with more frequent dose increases to accommodate for the...

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Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol

Cited by 79 publications

References 33 publications

Association of circulating PCSK9 concentration with cardiovascular metabolic markers and outcomes in stable coronary artery disease patients with or without diabetes: a prospective, observational cohort study

Association of circulating PCSK9 concentration with cardiovascular metabolic markers and outcomes in stable coronary artery disease patients with or without diabetes: a prospective, observational cohort study

Obesity and type 2 diabetes are associated with elevated PCSK9 levels in young women

Population Pharmacokinetic/Pharmacodynamic Analysis of Alirocumab in Healthy Volunteers or Hypercholesterolemic Subjects Using an Indirect Response Model to Predict Low-Density Lipoprotein Cholesterol Lowering: Support for a Biologics License Application Submission: Part II

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