scholarly journals Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment

2018 ◽  
Author(s):  
Eeva Sliz ◽  
Johannes Kettunen ◽  
Michael V Holmes ◽  
Clare Oliver-Williams ◽  
Charles Boachie ◽  
...  
Keyword(s):  
Amino Acids ◽  
Statin Therapy ◽  
Lipid Composition ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Statin Treatment ◽  
Metabolic Effects ◽  
Lipid Lowering ◽  
Low Density ◽  
Pcsk9 Inhibitors

ABSTRACTBackgroundBoth statins and PCSK9 inhibitors lower blood low-density lipoprotein cholesterol (LDL-C) levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these two lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial, and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial.Methods228 circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5,359 individuals (2,659 on treatment) in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial at 6-months post-randomization. The corresponding metabolic measures were analyzed in eight population cohorts (N=72,185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors.ResultsScaled to an equivalent lowering of LDL-C, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R2=0.88). Alterations in lipoprotein lipid composition and fatty acid balance were similar. However, discrepancies were observed for very-low-density lipoprotein (VLDL) lipid measures. For instance, genetic inhibition of PCSK9 showed weaker effects on lowering of VLDL-cholesterol compared with statin therapy (54% vs. 77% reduction, relative to the lowering effect on LDL-C; P=2 × 10−7 for heterogeneity). Genetic inhibition of PCSK9 showed no robust effects on amino acids, ketones, and a marker of inflammation (GlycA); in contrast, statin treatment lowered GlycA levels.ConclusionsGenetic inhibition of PCSK9 results in similar metabolic effects as statin therapy across a detailed lipid and metabolite profile. However, for the same lowering of LDL-C, PCSK9 inhibitors are predicted to be less efficacious than statins at lowering VLDL lipids, which could potentially translate into subtle differences in cardiovascular risk reduction.

scholarly journals The Role of PCSK9 Inhibitors in the Improvement of Outcomes in Patients after Acute Coronary Syndrome: Results of ODYSSEY OUTCOMES Trial

2019 ◽  
Vol 14 (6) ◽  
pp. 922-934 ◽  
Author(s):  
Yu. A. Karpov
Keyword(s):  
Acute Coronary Syndrome ◽  
Statin Therapy ◽  
High Intensity ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Pcsk9 Inhibitors ◽  
Coronary Syndrome

The aim of this review was to present the recently published results of ODYSSEY OUTCOMES trial and discuss the clinical perspective of these data. Patients with acute coronary syndrome are at very high risk of recurrent ischemic cardiovascular complications, especially during the first year after the event. The use of high-intensity statin therapy in this group of patients does not always lead to the achievement of target levels of atherogenic lipoproteins. PCSK9 inhibitors, administered in addition to statins, can provide additional reduction of low-density lipoprotein cholesterol, which leads to further improvements of outcomes in patients with atherosclerotic cardiovascular disease. According to the latest results from ODYSSEY OUTCOMES trial, among patients with recent acute coronary syndrome, who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who were treated with alirocumab then among those who received placebo. The treatment with alirocumab in patients with recent acute coronary syndrome was associated with reduction in death from any causes. The absolute risk reduction with alirocumab was the most prominent in the subpopulation of patients with low-density lipoprotein cholesterol ≥2,6 mmol/l at baseline. These results have implication for clinical practice and may play an important role for the improvement of outcomes in patients at highest cardiovascular risk after acute cardiovascular syndrome.

Importance of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in the treatment of dyslipidemia and atherosclerosis

2019 ◽  
pp. 40-52
Author(s):  
Maksim Maksimov ◽  
Anastasia Shikaleva ◽  
Aleksandra Kuchaeva
Keyword(s):  
Clinical Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Blood Lipid ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Low Density ◽  
Pcsk9 Inhibitors ◽  
Lipid Lowering Drugs ◽  
Antibody Preparations

Representatives of different groups of lipid-lowering drugs may have some differences in the nature and severity of the effect on the blood lipid spectrum. A new class of drugs, PCSK9 inhibitors, whose activity is associated with a protein involved in the control of low density lipoprotein receptors, has recently appeared. In clinical practice, this group is represented by monoclonal antibody preparations evolocumab and alirocumab. PCSK9 inhibitors are promising drugs for use in combination lipid-lowering therapy, which so far, given the results of clinical studies, can be recommended in the third place after statins and ezetimibe. In clinical studies, it was shown that alirocoumab and evolocumab alone or in combination with statins and/or other lipid-lowering drugs significantly reduce cholesterol levels in low density lipoproteins – by an average of 60%, depending on the dose.

ID: 1: STATINS DECREASE MORTALITY RATE AND LENGTH OF HOSPITALIZATION IN HEART FAILURE PATIENTS

2016 ◽  
Vol 64 (4) ◽  
pp. 917.2-918
Author(s):  
H Alkhawam ◽  
J Sall ◽  
JJ Lieber ◽  
TJ Vittorio ◽  
M Kabach
Keyword(s):  
Heart Failure ◽  
Mortality Rate ◽  
Statin Therapy ◽  
Readmission Rate ◽  
Therapy Group ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lower Mortality ◽  
Lipid Lowering ◽  
Low Density

IntroductionMany theories and clinical trials have attempted to address the effect of low-density lipoprotein (LDL) lowering in chronic congestive heart failure (CHF). Several studies have demonstrated that higher lipid and lipoprotein levels, including total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides, are associated with significantly improved outcomes in HF of both ischemic and nonischemic etiologies.HypothesisIn light of the association between high cholesterol levels and improved survival in HF, statin or other lipid-lowering therapy in HF remains controversial. In this study we evaluated the outcome of statins use in HF patients.MethodWe performed a retrospective chart analysis of 1,616 patients who were admitted to the hospital from 2005 to 2012 due to decompensated HF. 781 patients had HFrEF and 780 patients had HFpEF. The medications of all patients with HFrEF and HFpEF were reviewed. Each of HFrEF and HFpEF patients were divided into two groups: Statin-treated and non-Statin treated. The 30-day readmission rate, mortality rate and LOS were subsequently determined.ResultsOf the 1616 patients with decompensated HF, 776 patients had heart failure with preserved ejection fraction [HFpEF] and 780 patients had HFrEF. After the medications for each group were standardized, the 30-day readmission rate and mortality rate in the HFpEF versus HFrEF groups who received statin therapy did not differ (p=0.9 and 0.3, respectively).The HFpEF patients who received statin therapy had a lower mortality rate comparing to the non-statin therapy group (OR: 0.2, 95% CI: 0.1–0.5, p<0.001). Furthermore, LOS was significantly lower in the HFpEF statin therapy group 5.4 days versus 6.8 days in the HFpEF non-statin group (p<0.001). 30-day readmission rate did not differ between the two groups (p=0.9).The HFrEF patients who received statin therapy had a lower mortality rate comparing to HFrEF patients who did not receive statin therapy (OR: 0.3, 95% CI: 0.1–0.6, p<0.001). Additionally, LOS was significantly lower in the HFrEF statin therapy group 5.4 days versus 7 days in the HFrEF non-statin therapy group (p=0.04). 30-day readmission rate did not differ between the two groups (p=0.9).ConclusionOur study showed that statin therapy was associated with both a lower mortality rate and LOS among both HFpEF and HFrEF patients. However, the benefit of statin use on 30-day readmission rate did not differ between the two groups of HF patients.

scholarly journals Inclisirán as an alternative treatment for Hypercholesterolemia

2021 ◽  
Vol 12 (3) ◽  
pp. 517-521
Author(s):  
Jorge Andrés Ojeda Villota ◽  
Javier Alfredo Pérez Martínez ◽  
Luis Alberto Burgos de Moya ◽  
Rodrigo Alfonso Chavez Vega ◽  
Roxana Rivera Valencia ◽  
...  
Keyword(s):  
Risk Factors ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Low Density ◽  
Pcsk9 Inhibitors ◽  
Cholesterol Levels ◽  
Lowering Therapy

Hypercholesterolemia (CH) is defined as the elevation of serum cholesterol levels, especially low-density lipoprotein (LDL) cholesterol, which is considered to be one of the most relevant risk factors for triggering cardiovascular disease, for This is vitally important to start treatment, there are several highly useful pharmacological groups for lipid-lowering therapy, among them we highlight the PCSK9 inhibitors, among the molecules that are part of this group we find inclisirán, this being a structure that promises a lot in regarding the management of hypercholesterolemia.

scholarly journals Risk of Recurrent Coronary Events in Patients With Familial Hypercholesterolemia; A 10-Years Prospective Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Kjell-Erik Arnesen ◽  
Ann Vinh Phung ◽  
Karoline Randsborg ◽  
Irene Mork ◽  
Marlene Thorvall ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Statin Treatment ◽  
Term Treatment ◽  
Lipid Lowering ◽  
Treat To Target ◽  
Atherosclerotic Cardiovascular Disease ◽  
Pcsk9 Inhibitors ◽  
Long Term Treatment

Background and Aim: Real world evidence on long term treatment of patients with familial hypercholesterolemia (FH) is important. We studied the effects of intensive lipid lowering medication (LLM) and optimized lifestyle in the study TTTFH–Treat To Target FH.Materials and Methods: Adults with a first known total cholesterol of mean (95% CI) 9.8 mmol/L (9.5, 10.1) were included consecutively in their routine consultation during 2006. Of the patients 86.4% had a pathogenic FH-mutation and the remaining were clinically diagnosed. We included 357 patients and 279 met for follow-up after median 10.0 (min 8.1, max 12.8) years.Results: Mean (95% CI) low density lipoprotein (LDL-C) was reduced from 3.9 (3.8, 4.1) to 3.0 (2.9, 3.2). More men than women used high intensity statin treatment, 85.2 and 60.8%, respectively. Women (n = 129) had higher LDL-C; 3.3 mmol/L (3.0, 3.5), than men; (n = 144) 2.8 mmol/L (2.6, 3.0), p = 0.004. Add-on PCSK9 inhibitors (n = 25) reduced mean LDL-C to 2.0 (1.4, 2.6) mmol/L. At enrollment 57 patients (20.4%) had established atherosclerotic cardiovascular disease (ASCVD), and 46 (80.4%) of them experienced a new event during the study period. Similarly, 222 (79.6%) patients had no detectable ASCVD at enrollment, and 29 of them (13.1%) experienced a first-time event during the study period.Conclusion: A mean LDL-C of 3.0 mmol/L was achievable in FH, treated intensively at a specialized clinic with few users of PCSK9 inhibitors. LDL-C was higher (0.5 mmol/L) in women than in men. In patients with ASCVD at enrollment, most (80.7%) experienced a new ASCVD event in the study period. The FH patients in primary prevention had more moderate CV risk, 13% in ten years.

scholarly journals Adoption of PCSK9 Inhibitors Among Patients With Atherosclerotic Disease

2021 ◽  
Author(s):  
Elias J. Dayoub ◽  
Lauren A. Eberly ◽  
Ashwin S. Nathan ◽  
Sameed Ahmed M. Khatana ◽  
Srinath Adusumalli ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Pcsk9 Inhibitors ◽  
Pcsk9 Inhibitor ◽  
Number Of Patients

Background PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors represent a promising class of lipid‐lowering therapy, although their use has been limited by cost concerns. Methods and Results A retrospective cohort study was conducted using a nationwide commercial claims database comprising patients with atherosclerotic cardiovascular disease (ASCVD), aged 18 to 64 years. We identified the number of patients with ASCVD started on a PCSK9 inhibitor from the dates of US Food and Drug Administration approval in quarter 3 2015 through quarter 2 2019. Secondary objectives identified the proportions of patients started on a PCSK9 inhibitor in various ASCVD risk groups based on statin use and baseline low‐density lipoprotein cholesterol. We identified 126 419 patients with ASCVD on either PCSK9 inhibitor or statin therapy. Among these patients, 1168 (0.9%) filled a prescription for a PCSK9 inhibitor. The number of patients initiating a PCSK9 inhibitor increased from 2 patients in quarter 3 2015 to 119 patients in quarter 2 2019, corresponding to an increase from 0.05% to 2.5% of patients with ASCVD already on statins who started PCSK9 inhibitor therapy. Of patients with ASCVD with high adherence to a high‐intensity statin, 13 643 had low‐density lipoprotein cholesterol ≥70 mg/dL, and in this subgroup, 119 (0.9%) patients initiated a PCSK9 inhibitor. Conclusions Few patients started PCSK9 inhibitors from 2015 through mid‐2019, despite increasing trial evidence of efficacy, guidelines recommending PCSK9 inhibitors in high‐risk patients with ASCVD, and price reductions during this period. The magnitude of price reductions may not yet be sufficient to influence use management strategies aimed to limit PCSK9 inhibitor use.

PCSK9 Inhibitors: Novel Therapeutic Strategies for Lowering LDLCholesterol

2018 ◽  
Vol 19 (2) ◽  
pp. 165-176 ◽  
Author(s):  
Yan Wang ◽  
Zhao-Peng Liu
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Maximum Tolerated Dose ◽  
Therapeutic Strategies ◽  
Low Density ◽  
Pcsk9 Inhibitors ◽  
Cvd Risk ◽  
Safety Issues ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

Statins are currently the major therapeutic strategies to lower low-density lipoprotein cholesterol (LDL-C) levels. However, a number of hypercholesterolemia patients still have a residual cardiovascular disease (CVD) risk despite taking the maximum-tolerated dose of statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein receptor (LDLR), inducing its degradation in the lysosome and inhibiting LDLR recirculating to the cell membranes. The gain-offunction mutations in PCSK9 elevate the LDL-C levels in plasma. Therefore, PCSK9 inhibitors become novel therapeutic approaches in the treatment of hypercholesterolemia. Several PCSK9 inhibitors have been under investigation, and much progress has been made in clinical trials, especially for monoclonal antibodies (MoAbs). Two MoAbs, evolocumab and alirocumab, are now in clinical use. In this review, we summarize the development of PCSK9 inhibitors, including antisense oligonucleotides (ASOs), small interfering RNA (siRNA), small molecule inhibitor, MoAbs, mimetic peptides and adnectins, and the related safety issues.

Efficacy and Safety of Evolocumab in Reducing Low Density Lipoprotein Cholesterol Levels in Chinese Patients with Non-ST-segment Elevation Acute Coronary Syndrome

2020 ◽  
Vol 18 ◽  
Author(s):  
Xiaohan Xu ◽  
Meng Chai ◽  
Yujing Cheng ◽  
Pingan Peng ◽  
Xiaoli Liu ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Statin Treatment ◽  
Chinese Patients ◽  
Lipid Lowering ◽  
Control Group ◽  
Lipid Lowering Therapy ◽  
St Segment Elevation ◽  
Coronary Syndrome ◽  
St Segment

Aims: To explore early intensive lipid-lowering therapy in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Background: Lowering low-density lipoprotein cholesterol (LDL-C) levels can reduce cardiovascular morbidity and mortality in patients with atherosclerotic cardiovascular disease. Due to many reasons, the need for early intensive lipid-lowering therapy is far from being met in Chinese NSTE-ACS patients at high-risk of recurrent ischaemic events. Objective: To evaluate the feasibility, safety and efficacy of starting evolocumab in hospital to lower LDL-C levels in Chinese patients with NSTE-ACS. Methods: In this prospective cohort study initiated by researchers, 334 consecutive patients with NSTE-ACS who had sub-standard LDL-C levels (LDL-C ≥2.3 mmol/L after regular oral statin treatment for at least 4 weeks; or LDL-C ≥3.2 mmol/L without regular oral statin treatment) were included. Patients who agreed to treatment with evolocumab (140 mg subcutaneously every 2 weeks, initiated in hospital and used for 12 weeks after discharge) were enrolled in the evolocumab group (n=96) and others in the control group (n=238). All enrolled patients received regular statin treatment (atorvastatin 20 mg/day or rosuvastatin 10 mg/day; doses unchanged throughout the study).The primary endpoint was the change in LDL-C levels from baseline to week 12. Results: Most patients (67.1%) had not received regular statin treatment before. In the evolocumab group, LDL-C levels decreased significantly at week 4 and remained stable at week 8 and 12 (all p<0.001). At week 12, the LDL-C percentage change from baseline in the evolocumab group was -79.2±12.7% (from an average of 3.7 to 0.7 mmol/L), while in the control group it was -37.4±15.4% (from an average of 3.3 to 2.0 mmol/L). The mean difference between these 2 groups was -41.8% (95% CI -45.0 to -38.5%; p<0.001). At week 12, the proportions of patients with LDL-C levels <1.8 mmol/L and 1.4 mmol/L in the evolocumab group were significantly higher than in the control group (96.8 vs 36.1%; 90.6 vs 7.1%; both p<0.001). The incidence of adverse events and cardiovascular events was similar in both groups. Conclusions: In this prospective cohort study we evaluated the early initiation of evolocumab in NSTE-ACS patients in China. Evolocumab combined with statins significantly lowered LDL-C levels and increased the probability of achieving recommended LDL-C levels, with satisfactory safety and well tolerance.

scholarly journals Effects of Weight Gain after 20 Years of Age and Incidence of Hyper-Low-Density Lipoprotein Cholesterolemia: The Iki Epidemiological Study of Atherosclerosis and Chronic Kidney Disease (ISSA-CKD)

2021 ◽  
Vol 10 (14) ◽  
pp. 3098
Author(s):  
Shota Okutsu ◽  
Yoshifumi Kato ◽  
Shunsuke Funakoshi ◽  
Toshiki Maeda ◽  
Chikara Yoshimura ◽  
...  
Keyword(s):  
Weight Gain ◽  
General Population ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Population Based ◽  
Lipid Lowering ◽  
Low Density ◽  
Obesity Hypertension ◽  
Old Men

The aim of this study was to investigate the effects of long-term weight gain from the age of 20 on incidence of hyper-low-density-lipoprotein (LDL) cholesterolemia in the general population of Japanese people. Methods: We conducted a population-based retrospective cohort study using annual health checkup data for residents of Iki City, Nagasaki Prefecture, Japan. A total of 3179 adult (≥30 years old) men and women without hyper-LDL cholesterolemia at baseline, who underwent two or more health checkups were included in the analysis. Information on weight gain (≥10 kg) after 20 years of age was obtained using questionnaire. The outcome of this study was development of hyper-LDL cholesterolemia defined as LDL-cholesterol level ≥3.62 mmol/L and/or initiation of lipid-lowering medications. Results: During a mean follow-up period of 4.53 years, 665 of the 3179 participants developed hyper-LDL cholesterolemia (46.5/1000 person-years). The incidence of hyper-LDL cholesterolemia was higher in participants with a weight gain of ≥10 kg (55.3/1000 person-years) than among those with a weight gain of <10 kg (41.8/1000 person-years). This association remained statistically significant even after adjustment for age, sex, smoking, daily drinking, exercise, obesity, hypertension, and diabetes (multivariable hazard ratio 1.31, 95% confidence interval 1.08–1.58, p = 0.006). Conclusion: A weight gain of ≥10 after 20 years of age affected the development of hyper-LDL cholesterol regardless of age, sex, and obesity in a general population of Japanese.

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