Evolocumab

Importance: Recent studies have shown that Friedewald underestimates low-density lipoprotein cholesterol (LDL-C) at lower levels, which could result in undertreatment of high-risk patients. A novel method (Martin/Hopkins) using a patient-specific conversion factor provides more accurate LDL-C levels. However, this method has not been tested in proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor-treated patients. Objective: To investigate accuracy of 2 different methods for estimating LDL-C levels (Martin/Hopkins and Friedewald) compared with gold standard preparative ultracentrifugation (PUC) in patients with low LDL-C levels in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk (FOURIER) trial...

Dyslipidemia, and specifically elevated low-density lipoprotein (LDL) cholesterol, is one of the most important cardiovascular risk factors. Statins are considered first line therapy for the primary and secondary prevention of cardiovascular disease. However, statins may not be adequate treatment for elevated circulating LDL levels and are ineffective in certain familial hypercholesterolemias. The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulatory protein that affects LDL receptors, offers a new alternative for these patients...

OBJECTIVE: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) and statins are known to lower plasma LDL (low-density lipoprotein)-cholesterol concentrations. However, the comparative effects of these treatments on the postprandial metabolism of TRLs (triglyceride-rich lipoproteins) remain to be investigated. APPROACH AND RESULTS: We performed a 2-by-2 factorial trial of the effects of 8 weeks of subcutaneous evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on postprandial TRL metabolism in 80 healthy, normolipidemic men after ingestion of an oral fat load...

PURPOSE: The efficacy, safety, and place in therapy of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for lipid lowering are reviewed. SUMMARY: PCSK9 inhibitors are injectable monoclonal antibodies that increase the availability of low-density lipoprotein (LDL) receptors, resulting in a reduction in serum LDL cholesterol (LDL-C). The currently available PCSK9 inhibitors alirocumab and evolocumab were shown to reduce LDL-C concentrations by approximately 55-60% relative to placebo use when used as monotherapy or added to other lipid-lowering therapies...

Atherosclerotic cardiovascular diseases (ASCVDs) are associated with a substantial mortality, physical morbidity, and mental disability. Elevated plasma low-density lipoprotein cholesterol (LDL-C) levels play a major role in the pathophysiology of ASCVDs. Statins have been shown to reduce ASCVD risk and associated events and are recommended as first-line therapy for treatment of hypercholesterolemia by current international guidelines. The key issue is to attain guideline-recommended LDL-C levels (below 70 mg/dl) for patients at very high cardiovascular risk...

BACKGROUND: Familial hypercholesterolemia is a genetic lipoprotein disorder characterized by elevated plasma low-density lipoprotein cholesterol level, (tendinous xanthomas, xanthelasmas, and premature arcus corneus) and early onset atherosclerotic cardiovascular disease. Familial hypercholesterolemia is caused by mutations in the low-density lipoprotein receptor, apolipoprotein B or proprotein convertase subtilisin/kexin type 9 genes. Rare mutations in low-density lipoprotein receptor adapter protein 1, APOE p...

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab reduces low-density lipoprotein cholesterol (LDL-C) and the risk of cardiovascular events. OBJECTIVES: To compare LDL-C reduction using evolocumab 140 mg once every 2 weeks (Q2W) or 420 mg monthly (QM) versus lower doses (70 mg Q2W or 280 mg QM) or placebo. METHODS: Patients received evolocumab 70 or 140 mg Q2W, 280 or 420 mg QM, or placebo Q2W or QM in two 12-week phase 2 studies: one with and one without statins...

Diabetes is associated with increased cardiovascular disease (CVD) risk. Previous studies with statins have established that a 1 mmol/l reduction in LDL-cholesterol reduces CVD events by 21% over 5 years in people with diabetes. More recently, trials in people with acute coronary syndromes showed that ezetimibe reduced CVD events by 6% at 5 years and achieved a LDL-cholesterol of 1.6 mmol/l with better results in people with Type 2 diabetes. Several novel lipid-lowering therapies have recently been developed...

Evolocumab, a novel human monoclonal antibody, inhibits proprotein convertase subtilisin/kexin type 9, a protein that targets low-density lipoprotein-cholesterol (LDL-C) receptors for the treatment of hyperlipidemia. The primary objective of this analysis was to characterize the population pharmacokinetics (popPK) and exposure-response relationship of evolocumab to assess if dose adjustment is needed across differing patient populations. Data were pooled for 5474 patients in 11 clinical studies who received evolocumab doses of 7-420 mg at various frequencies, either intravenously or subcutaneously...

In 2015, the US Food and Drug Administration (FDA) approved the anti-proprotein convertase subtilsin/kexin type 9 (PCSK9) monoclonal antibodies, alirocumab and evolocumab, to treat patients with hypercholesterolemia and mixed dyslipidemia. Since then, considerable attention has been paid to the use of these monoclonal antibodies for the treatment of diabetic dyslipidemia with a goal of reducing the risk for cardiovascular disease. Recently, consensus statements on the clinical use of PCSK9 inhibitors in patients with type 2 diabetes mellitus, who are unable to achieve the goal of low-density lipoprotein cholesterol (<70 mg/dL or <1...

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-of-function mutations in PCSK9 elevate the LDL-C levels in plasma...

BACKGROUND: Evolocumab is an expensive proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor which has been shown to significantly improve cardiovascular outcomes in high risk patients. METHODS: This is a case study describing a stepwise approach to "PCSK9 inhibitor non-response" in a patient with familial hypercholesterolaemia. There are a few described pathophysiological mechanisms for "PCSK9 inhibitor non-response" including homozygous LDL-C receptor-negative mutations and alteration in the binding site of PCSK9 inhibitors...

OBJECTIVE: To evaluate the efficacy, safety, and cost-effectiveness of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and describe its place in therapy for the treatment of hypercholesterolemia. DATA SOURCES: A search of MEDLINE, CINAHL, and Clinicaltrials.gov was performed from January 2012 to March 2018 to identify literature pertaining to PCSK9 inhibitors using pre-specified search terms. Additional references were identified from citations of the literature...

OBJECTIVE: To summarize 10 high-quality studies from 2017 that have strong relevance to primary care practice. QUALITY OF EVIDENCE: Study selection involved routine literature surveillance by a group of primary care health professionals. This included screening abstracts of important journals and Evidence Alerts, as well as searching the American College of Physicians Journal Club. MAIN MESSAGE: Topics of the 2017 articles include whether treating subclinical hypothyroidism improves outcomes or symptoms; whether evolocumab reduces cardiovascular disease as well as low-density lipoprotein levels; whether lifestyle interventions reduce medication use in patients with diabetes; whether vitamin D prevents cardiovascular disease, cancer, or upper respiratory tract infections; whether canagliflozin reduces clinical events in patients with diabetes; how corticosteroid injections affect knee osteoarthritis; whether drained abscesses benefit from antibiotic treatment; whether patients with diabetes benefit from bariatric surgery; whether exenatide reduces clinical events in patients with diabetes; and whether tympanostomy tubes affect outcomes in recurrent acute otitis media or chronic otitis media...

We report the case of a patient with probable heterozygous familial hypercholesterolemia and mitotane-induced resistant hypercholesterolemia, despite combination therapy with rosuvastatin and ezetimibe. The patient was managed with the addition of evolocumab. Use of a proprotein convertase subtilisin-kexin type 9 inhibitor, should be considered in patients who develop mitotane-related hypercholesterolemia that cannot be managed with conventional lipid-lowering treatment.

Background -The FOURIER trial recently showed that the PCSK9 inhibitor evolocumab significantly reduced major vascular events in patients with stable atherosclerotic cardiovascular disease, including patients with prior MI. Within the broad group of patients with prior MI, we hypothesized that readily ascertainable features would identify subsets that derive greater clinical risk reduction with evolocumab. Methods -The 22,351 patients with a prior MI were characterized based on time from most recent MI, number of prior MIs, and presence of residual multivessel coronary artery disease (≥40% stenosis in ≥2 large vessels)...

BACKGROUND: Evolocumab, a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, has been shown to reduce low-density lipoprotein levels by up to 60%. Despite the absence of a reduction in overall or cardiovascular mortality in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, some believe that, with longer treatment, such a benefit might eventually be realized. Our aim was to estimate the potential mortality benefit over a patient's lifetime and the cost per year of life saved (YOLS) for an average Canadian with established coronary artery disease...

Aims: Lipoprotein(a) [Lp(a)], a low-density lipoprotein (LDL) particle covalently bound to apolipoprotein(a) [apo(a)], is a potentially potent heritable risk factor for cardiovascular disease. We investigated the mechanism whereby evolocumab, a monoclonal antibody against proprotein convertase subtilisin-kexin type 9 (PCSK9), lowers Lp(a). Methods and results: We studied the kinetics of Lp(a) particles in 63 healthy men, with plasma apo(a) concentration >5 nmol/L, participating in an 8-week factorial trial of the effects of evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on lipoprotein metabolism...

PURPOSE OF REVIEW: A number of novel trials have assessed the efficacy of new lipid-lowering therapies in cardiovascular disease (CVD). RECENT FINDINGS: Proprotein convertase subtilisin kexin-9 inhibitors reduce low-density lipoprotein cholesterol (LDL-C) by 50-55%. A CVD outcome trial in patients with acute coronary syndromes with evolocumab achieved a LDL-C of 0.8 mmol/l (31 mg/dl) and a 20% relative risk reduction in CVD events in 2.2 years. Cholesterol ester transfer protein inhibitors raise high-density lipoprotein cholesterol and can lower LDL-C...

BACKGROUND: The reduction of cholesterol levels with cholesterol-lowering therapy may improve endothelial function. Lipid-lowering therapy has been greatly enhanced by the introduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies. Less is known of the effect of PCSK9 inhibitors on endothelial function of subjects with hypercholesterolemia. OBJECTIVE: To assess whether treatment with PCSK9 inhibitors may improve endothelial function evaluated by brachial artery vasoreactivity test...