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PCSK9 inhibitors: a non-statin cholesterol-lowering treatment option.
Pokrywka, GS
Postgraduate medicine. 2018;(3):287-298
Abstract
Elevated low-density lipoprotein cholesterol (LDL-C) plays a major role in the development of atherosclerotic cardiovascular disease. Statins are the first-line treatment to lower LDL-C in patients with hypercholesterolemia; however, some high cardiovascular risk patients may have inadequate responses to statin therapy or are intolerant to statins, and may need additional and/or alternative non-statin therapies to further reduce their LDL-C levels. Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of circulating LDL-C levels, have received considerable attention as promising non-statin therapeutic options for the management of hypercholesterolemia. This review provides a brief overview of the history and science of PCSK9 inhibitors, focusing on two PCSK9 monoclonal antibodies that have been approved by the US Food and Drug Administration: alirocumab and evolocumab. Recently released and forthcoming clinical trial data will be discussed, as well as the practical application of patient populations that may benefit from PCSK9 inhibitors. Finally, the recent expert recommendations regarding the use of PCSK9 inhibitors and other non-statin therapies to treat patients with inadequate LDL-C-lowering on statin therapy will be summarized.
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A Brief Drug Class Review: Considerations for Statin Use, Toxicity, and Drug Interactions.
Wooten, JM
Southern medical journal. 2018;(1):39-44
Abstract
For approximately 30 years, statins have been effectively used to control cholesterol, thereby reducing the morbidity and mortality associated with cardiovascular disease. Evidence-based recommendations regarding how these drugs are dosed and used have changed significantly through the years. There are seven statins approved for use in the United States, and although the mechanism of action pertaining to cholesterol reduction is the same for all statins, each has its own specific pharmacologic profile. One unique aspect of statin dosing is understanding the potential drug interactions associated with statin use; interactions can occur with all statins, but the mechanism and type of interaction can vary significantly among drugs. These interactions can result in significant elevations in statin blood concentrations, thereby increasing the risk of the adverse effects of statins, the most significant of which is muscle toxicity. Practitioners who care for patients receiving statins should understand the pharmacologic differences among these drugs, as well as the varied drug interaction potential that all statins possess.
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Cardiovascular Benefits of Phenol-Enriched Virgin Olive Oils: New Insights from the Virgin Olive Oil and HDL Functionality (VOHF) Study.
Pedret, A, Fernández-Castillejo, S, Valls, RM, Catalán, Ú, Rubió, L, Romeu, M, Macià, A, López de Las Hazas, MC, Farràs, M, Giralt, M, et al
Molecular nutrition & food research. 2018;(16):e1800456
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Abstract
SCOPE The main findings of the "Virgin Olive Oil and HDL Functionality" (VOHF) study and other related studies on the effect of phenol-enriched virgin olive oil (VOO) supplementation on cardiovascular disease are integrated in the present work. METHODS AND RESULTS VOHF assessed whether VOOs, enriched with their own phenolic compounds (FVOO) or with those from thyme (FVOOT), improve quantity and functionality of HDL. In this randomized, double-blind, crossover, and controlled trial, 33 hypercholesterolemic subjects received a control VOO (80 mg kg-1 ), FVOO (500 mg kg-1 ), and FVOOT (500 mg kg-1 ; 1:1) for 3 weeks. Both functional VOOs promoted cardioprotective changes, modulating HDL proteome, increasing fat-soluble antioxidants, improving HDL subclasses distribution, reducing the lipoprotein insulin resistance index, increasing endogenous antioxidant enzymes, protecting DNA from oxidation, ameliorating endothelial function, and increasing fecal microbial metabolic activity. Additional cardioprotective benefits were observed according to phenol source and content in the phenol-enriched VOOs. These insights support the beneficial effects of OO and PC from different sources. CONCLUSION Novel therapeutic strategies should increase HDL-cholesterol levels and enhance HDL functionality. The tailoring of phenol-enriched VOOs is an interesting and useful strategy for enhancing the functional quality of HDL, and thus, it can be used as a complementary tool for the management of hypercholesterolemic individuals.
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Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.
Willeit, P, Ridker, PM, Nestel, PJ, Simes, J, Tonkin, AM, Pedersen, TR, Schwartz, GG, Olsson, AG, Colhoun, HM, Kronenberg, F, et al
Lancet (London, England). 2018;(10155):1311-1320
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Abstract
BACKGROUND Elevated lipoprotein(a) is a genetic risk factor for cardiovascular disease in general population studies. However, its contribution to risk for cardiovascular events in patients with established cardiovascular disease or on statin therapy is uncertain. METHODS Patient-level data from seven randomised, placebo-controlled, statin outcomes trials were collated and harmonised to calculate hazard ratios (HRs) for cardiovascular events, defined as fatal or non-fatal coronary heart disease, stroke, or revascularisation procedures. HRs for cardiovascular events were estimated within each trial across predefined lipoprotein(a) groups (15 to <30 mg/dL, 30 to <50 mg/dL, and ≥50 mg/dL, vs <15 mg/dL), before pooling estimates using multivariate random-effects meta-analysis. FINDINGS Analyses included data for 29 069 patients with repeat lipoprotein(a) measurements (mean age 62 years [SD 8]; 8064 [28%] women; 5751 events during 95 576 person-years at risk). Initiation of statin therapy reduced LDL cholesterol (mean change -39% [95% CI -43 to -35]) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex (vs <15 mg/dL) were 1·04 (95% CI 0·91-1·18) for 15 mg/dL to less than 30 mg/dL, 1·11 (1·00-1·22) for 30 mg/dL to less than 50 mg/dL, and 1·31 (1·08-1·58) for 50 mg/dL or higher; respective HRs for on-statin lipoprotein(a) were 0·94 (0·81-1·10), 1·06 (0·94-1·21), and 1·43 (1·15-1·76). HRs were almost identical after further adjustment for previous cardiovascular disease, diabetes, smoking, systolic blood pressure, LDL cholesterol, and HDL cholesterol. The association of on-statin lipoprotein(a) with cardiovascular disease risk was stronger than for on-placebo lipoprotein(a) (interaction p=0·010) and was more pronounced at younger ages (interaction p=0·008) without effect-modification by any other patient-level or study-level characteristics. INTERPRETATION In this individual-patient data meta-analysis of statin-treated patients, elevated baseline and on-statin lipoprotein(a) showed an independent approximately linear relation with cardiovascular disease risk. This study provides a rationale for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials. FUNDING Novartis Pharma AG.
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Comparisons of three different doses of alirocumab application in patients with hypercholesterolemia: a meta-analysis.
Zhang, YS, Hao, YH, Luo, HL, Xie, BC, Fu, JY, Zhou, ZK
Minerva medica. 2018;(3):229-238
Abstract
INTRODUCTION Low high-density lipoprotein cholesterol (HDL-C) and high low-density lipoprotein cholesterol (LDL-C) levels are associated with incidence of cardiovascular disease (CVD). Alirocumab has been considered as an efficacious, safe and promising therapeutic modality for hypercholesterolemia. The purpose of this study is to compare the differences of the three different doses of alirocumab in patients with hypercholesterolemia. EVIDENCE ACQUISITION Randomized controlled trials were identified from PubMed, EMBASE, PMC and Cochrane-library databases. The inter-comparison of different doses were performed by subgroups analysis. Meta-analyses were performed by the Review Manager 5.3 and STATA 13.0 software. EVIDENCE SYNTHESIS A total of nine studies involving 3870 patients were included in this meta-analysis. Alirocumab administered at 75-150 mg every 2 weeks (Q2W) resulted in a greater percent change from baseline in LDL-C concentrations (MD, -55.17; 95% CI: -64.35 to -45.99; P<0.05), and HDL-C levels (MD, 7.70; 95% CI 5.94 to 9.46; P<0.05) than other two doses (300 mg every 4 weeks [Q4W], 150 mg every 2 weeks [Q2W]). There was no difference in achieving the treatment goal of LDL-C (≤1.8 mmol/L), in other serum lipid parameters (total cholesterol [TC], triglyceride [TG]), and in the incidence of adverse events. CONCLUSIONS The results demonstrate that alirocumab at a dose of 75-150 mg Q2W should be preferred in patients with hypercholesterolemia.
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Clinical Inquiries. How often does long-term PPI therapy cause clinically significant hypomagnesemia?
Plaut, T, Graeme, K, Stigleman, S, Hulkower, S, Woodall, T
The Journal of family practice. 2018;(9):576-577
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A Novel Cause of Familial Hypercholesterolemia: PCSK9 Gene Duplication.
Paquette, M, Baass, A
The Canadian journal of cardiology. 2018;(10):1259-1260
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New and Future Parenteral Therapies for the Management of Lipid Disorders.
Garcia, R, Burkle, J
Archives of medical research. 2018;(8):538-547
Abstract
Cardiovascular disease (CVD) is the leading cause of death in the world. According to the World Health Organization, an estimated 17.9 million people died from CVD in 2016, representing 31% of all global deaths. Of these deaths, 5% are due to myocardial infarction and stroke. Dyslipidemia is known as the major risk factor of atherosclerotic cardiovascular disease. With current therapies, about 60% of high-risk CVD patients do not achieve LDL-C goals, and in patients with familiar hypercholesterolemia (FH) at maximum intensity statin treatment, only 20% achieve LDL-C goals. We discuss new and future parenteral therapies for the management of lipid disorders.
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Effect of alirocumab on coronary atheroma volume in Japanese patients with acute coronary syndromes and hypercholesterolemia not adequately controlled with statins: ODYSSEY J-IVUS rationale and design.
Ako, J, Hibi, K, Kozuma, K, Miyauchi, K, Morino, Y, Shinke, T, Tsujita, K, Uno, K, Kawabata, Y, Hiro, T
Journal of cardiology. 2018;(6):583-589
Abstract
BACKGROUND Serial intravascular ultrasound (IVUS) imaging can be used to evaluate the effect of cholesterol-lowering on coronary atheroma progression and plaque volume, with evidence of potential incremental effects with more aggressive lipid-lowering treatments. Alirocumab is a highly specific, fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). This study will investigate the effect of alirocumab on coronary artery plaque volume in Japanese patients with a recent acute coronary syndrome (ACS) and hypercholesterolemia while on stable statin therapy. METHODS ODYSSEY J-IVUS is a phase IV, open-label, randomized, blinded IVUS analysis, parallel-group, multicenter study in Japanese adults recently hospitalized for an ACS and who have elevated low-density lipoprotein cholesterol (LDL-C) values [≥100mg/dL (2.6mmol/L)] at ACS diagnosis and suboptimal LDL-C control on stable statin therapy. Patients will be randomized (1:1) to receive alirocumab or standard-of-care (SOC). The alirocumab arm will receive alirocumab 75mg every 2 weeks (Q2W) added to statin therapy (atorvastatin ≥10mg/day or rosuvastatin ≥5mg/day), with a dose increase to 150mg Q2W in patients whose LDL-C value remains ≥100mg/dL at week 12. The SOC arm will receive atorvastatin ≥10mg/day or rosuvastatin ≥5mg/day, with dose adjustment to achieve LDL-C <100mg/dL. Post-treatment IVUS imaging will be done at week 36±2. The primary objective is to compare the effect of alirocumab versus SOC on coronary atheroma progression (percent change in normalized total atheroma volume) after 9 months of treatment. CONCLUSION ODYSSEY J-IVUS will provide insights into the effect of alirocumab on coronary atherosclerotic plaque volume in patients with a recent ACS and hypercholesterolemia while on stable statin therapy. ClinicalTrials.gov number: NCT02984982.
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A randomized, double-blind, placebo-controlled trial investigating cholesterol-lowering effects and safety of yellow yeast rice in adults with mild to moderate hypercholesterolemia: A study protocol.
Jeong, S, Lee, J, Kwon, O, Kim, JW, Oh, B
Medicine. 2018;(30):e11634
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Abstract
BACKGROUND Elevated levels of blood lipids are well-documented risk factors for cardiovascular disease. For cardiovascular risk reduction, preventive strategies to lower blood cholesterol levels are essential, and these strategies include lifestyle modification and cholesterol-lowering agents. We aim to investigate the cholesterol-lowering effects and safety of yellow yeast rice in a randomized, controlled, double-blind, and parallel group study. METHODS Participants for this study will be selected based on the following inclusion criteria:Participants are randomly allocated to the placebo or yellow-yeast-rice-treated group. Participants with mild to moderately elevated LDL-C levels will consume 1 pouch of yellow yeast rice powder (containing monacolin K) or placebo twice daily for 8 weeks. Next, the lipid profiles will be evaluated. RESULTS The number of participants required for this study is 68, and is currently recruiting participants. Participants are randomly assigned to control group and intervention group. CONCLUSION This is the first human intervention study to investigate the cholesterol-lowering effects and safety of yellow yeast rice in adults with mild to moderate hypercholesterolemia. Also, this is a randomized, double-blind, placebo-controlled trial that considers confounders, such as dietary habits, lifestyle factors, and genetic factors.