PCSK9 inhibitors in the prevention of cardiovascular disease.
ABSTRACT: Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) remains the cornerstone in the primary and secondary prevention of cardiovascular disease. However, lack of efficacy and adverse effects mean that a substantial proportion of patients fail to achieve acceptable LDL-C levels with currently available lipid-lowering drugs. Over the last decade, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic strategy to reduce residual cardiovascular disease risk. Binding of PCSK9 to the LDL receptor targets the receptor for lysosomal degradation. The recognition that inhibition of PCSK9 increases LDL receptor activity has led to the development of a number of approaches to directly target PCSK9. Numerous monoclonal antibodies against PCSK9 are currently being evaluated in phase 3 trials, involving various patient categories on different background lipid-lowering therapies. Current evidence shows reductions in LDL-C levels of up to 70 % may be achieved with PCSK9 inhibition, independent of background statin therapy. This review examines the most recent evidence and future prospects for the use of PCSK9 inhibitors in the prevention of cardiovascular disease.
Project description:The first monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have been approved for clinical use. This timely review highlights recent developments.Low-density lipoprotein cholesterol (LDL-C) is the primary driver of atherosclerosis and the key target for intervention. Yet despite best treatment including statins, attaining sufficient LDL-C lowering can be problematic for high cardiovascular risk patients. The development of PCSK9 inhibitors, driven by novel genetic and mechanistic insights, offers an answer. Removal of circulating PCSK9 increases LDL receptor availability, and thus markedly decreases plasma LDL-C levels (by ?50-60%), and is additive to the lipid lowering effects of statins and ezetimibe. PCSK9 inhibition also reduces (by 25-30%) plasma levels of lipoprotein(a), a causal factor in atherosclerotic vascular disease, suggestive of partial catabolism of lipoprotein(a) by LDL receptors. The ODYSSEY and PROFICIO (Programme to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations) clinical trial programmes involving a wide range of high-risk patients, including statin intolerant patients, have confirmed the consistency of the LDL response, even with concomitant high-intensity statin or nonstatin therapy. Extensive evidence to date attests to a favourable safety and tolerability profile for these innovative agents.The new pharmacotherapeutic era of PCSK9 inhibition is upon us, promising major reduction in cardiovascular events across a wide spectrum of high-risk patients.
Project description:PCSK9 proprotein convertase subtilisin/kexin type (PCSK9) is a crucial protein in LDL cholesterol (LDL-C) metabolism by virtue of its pivotal role in the degradation of the LDL receptor. In recent years, both in vitro and in vivo studies have greatly supplemented our understanding of the (patho)physiological role of PCSK9 in human biology. In the current review, we summarize studies published or in print before May 2012 concerning the physiological role of PCSK9 in cholesterol metabolism. Moreover, we briefly describe the clinical phenotypes encountered in carriers of mutations in the gene encoding PCSK9. As PCSK9 has emerged as a novel target for LDL-C lowering therapy, methods to inhibit PCSK9 will also be reviewed. Initial data from investigations of PCSK9 inhibition in humans are promising and indicate that PCSK9 inhibition may be a viable new therapeutic option for the treatment of dyslipidemia and associated cardiovascular diseases.
Project description:Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating enzyme of hepatic origin that plays a key role in LDL receptor turnover. Genetic studies have confirmed that individuals with gain-of-function PCSK9 mutations have increased PCSK9 activity, elevated LDL-cholesterol levels and a severe form of familial hypercholesterolaemia. Those with variants leading to reduced PCSK9 have lower LDL-cholesterol levels and a reduced risk of coronary heart disease, and this has led to the development of various strategies aimed at reducing circulating PCSK9. Monoclonal antibodies to PCSK9, given every 2-4 weeks by subcutaneous injection, have been shown to reduce LDL-cholesterol by 50-60% compared with placebo in individuals with and without diabetes. PCSK9 inhibition also reduces lipoprotein(a), an atherogenic lipid particle, by around 20-30%. Major cardiovascular outcome trials for two agents, evolocumab and alirocumab, are expected to report from 2017. These trials involve over 45,000 participants and are likely to include about 15,000 individuals with diabetes. PCSK9-binding adnectins have been employed as an alternative method of removing circulating PCSK9. Small interfering RNA targeting messenger RNA for PCSK9, which acts by reducing hepatic production of PCSK9, is also under investigation. These agents may only need to be given by subcutaneous injection once every 4-6 months. Ongoing trials will determine whether anti-PCSK9 antibody therapy safely reduces cardiovascular risk, although high cost may limit its use. Development of PCSK9-lowering technologies cheaper than monoclonal antibodies will be necessary for large numbers of individuals to benefit from this approach to lowering cholesterol.
Project description:Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases low-density lipoprotein cholesterol (LDL-C) concentrations through interference with normal physiologic hepatic LDL receptor (LDLR) recycling. Inhibiting PCSK9 results in improved LDLR recycling, increased LDLR availability on hepatocyte cell surfaces, and reduced blood LDL-C levels, making PCSK9 inhibition a novel therapeutic strategy for managing hypercholesterolemia. Monoclonal antibodies directed against PCSK9 have been developed for this purpose. A large number of clinical trials have demonstrated that monoclonal antibodies against PCSK9 yield substantial reductions in LDL-C when administered as monotherapy or in combination with statins to patients with nonfamilial and familial forms of hypercholesterolemia. Data from long-term trials demonstrate that the LDL-C-lowering effect of PCSK9 inhibitors is durable. These agents are generally well tolerated, and few patients discontinue treatment due to adverse events. Moreover, PCSK9 inhibitors do not appear to elicit the hepatic and muscle-related side effects associated with statin use. The ultimate value of PCSK9 inhibitors will be measured by their effect on clinical outcomes. Early evidence of a reduction in cardiovascular events after 1 year of treatment was shown in a prospective exploratory analysis of two ongoing long-term open-label extension evolocumab trials. Similarly, cardiovascular events were reduced in another exploratory analysis after >1 year of therapy with alirocumab. For the primary care physician, PCSK9 inhibitors represent a welcome additional option for lowering LDL-C in patients with familial forms of hypercholesterolemia and those with clinical atherosclerotic cardiovascular disease who are on maximally tolerated statin therapy.
Project description:For more than half a century, low-density lipoprotein cholesterol (LDL-C) has been recognized as a major risk factor for incident atherosclerotic cardiovascular disease. The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9) in 2003, which prevents LDL-C receptor recycling, identified a new target for drug intervention. Recently, two large-scale randomized clinical outcomes trials involving fully human anti-PCSK9 monoclonal antibodies tested the hypothesis that targeting this pathway would reduce cardiovascular events. Both the FOURIER (Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk) and ODYSSEY OUTCOMES trials met their primary efficacy endpoints, confirming findings reported earlier that major adverse cardiovascular events can be reduced by a further lowering of LDL-C beyond that achieved with statin therapy. In both trials, there were incremental reductions in LDL-C of > 50% from baseline, with no major safety concerns, over the trials' median follow-up time (2.2 and 2.8 years, respectively). While there were differences in design, lipid management and overall results, key messages from both studies were similar. However, post-publication, additional questions have arisen, especially regarding drug effects over the long-term, including a potential mortality benefit.
Project description:Review novel insights into the biology of proprotein convertase subtilisin/kexin 9 (PCSK9) that may explain the extreme efficiency of PCSK9 inhibition and the unexpected metabolic effects resulting from PCSK9 monoclonal antibody therapy, and may identify additional patients as target of therapy.For over 20 years, the practical knowledge of cholesterol metabolism has centered around cellular mechanisms, and around the idea that statin therapy is the essential step to control metabolic abnormalities for cardiovascular risk management. This view has been embraced by the recent AHA/ACC guidelines, but is being challenged by recent studies including nonstatin medications and by the development of a new class of cholesterol-lowering agents that seems destined to early US Food and Drug Administration approval. The discovery of PCSK9 - a circulating protein that regulates hepatic low-density lipoprotein (LDL) receptor and serum LDL cholesterol levels - has led to a race for its therapeutic inhibition. Recent findings on PCSK9 regulation and pleiotropic effects will help identify additional patient groups likely to benefit from the inhibitory therapy and unravel the full potential of PCSK9 inhibition therapy.Injectable human monoclonal antibodies to block the interaction between PCSK9 and LDL receptor are demonstrating extraordinary efficacy (LDL reductions of up to 70%) and almost the absence of any side-effects. A more moderate effect is seen on other lipoprotein parameters, with the exception of lipoprotein(a) levels. We describe mechanisms that can explain the effect on lipoprotein(a), predict a potential effect on postprandial triglyderides, and suggest a new category of patients for anti-PCSK9 therapy.
Project description:Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that is mainly expressed in the liver but can also be found in the intestine and kidneys. PCSK9 promotes the degradation of low density lipoprotein receptors (LDLR) by reducing their recycling and targeting the receptors for lysosomal destruction, thereby decreasing the rate of removal of LDL-cholesterol from the circulation. Thus, interventions targeting PCSK9 by reducing its expression may lead to significant reductions of LDL-cholesterol and possibly decrease cardiovascular risk. The present review aims to present and discuss the current clinical and scientific data pertaining to lipid-lowering interventions targeting PCSK9.
Project description:Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone for the prevention of atherosclerotic heart disease, improving clinical outcomes and reducing vascular mortality in patients with hypercholesterolemia. The clinical benefits of LDL-C reduction appear to extend even to patients starting with LDL-C as low as 60-80 mg/dL prior to initiating therapy. Statins are the first-line agents for treating hypercholesterolemia and are effective in reducing LDL-C, but many patients are unable to achieve their optimal lipid targets despite intensive statin therapy. Therefore, there has been a strong impetus for the development of novel pharmacologic agents designed to lower LDL-C further in patients already on statin therapy. Genetic mutations resulting in altered cholesterol homeostasis provide valuable information regarding novel approaches for treating hypercholesterolemia. To that end, mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) were linked to altered levels of LDL-C, illustrating this protein's role in lipid metabolism. PCSK9 promotes degradation of the LDL receptor, preventing its transport back to the cell surface and thereby increasing circulating LDL-C. Conversely, inhibition of PCSK9 can profoundly decrease circulating LDL-C, and thus is an attractive new target for LDL-C-lowering therapy. AMG 145 is a fully human monoclonal immunoglobulin G2 antibody that binds specifically to human PCSK9 and inhibits its interaction with the low-density lipoprotein receptor. In this manuscript, we describe the rationale and design of LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy-Thrombolysis In Myocardial Infarction 57 (LAPLACE-TIMI 57; NCT01380730), a 12-week, randomized, double-blind, dose-ranging, placebo-controlled study designed to assess the safety and efficacy of AMG 145 when added to statin therapy in patients with hypercholesterolemia.
Project description:Barely a decade after the discovery of the gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and its recognition as a key player in cholesterol metabolism, PCSK9 inhibition is now considered an exciting approach in the reduction of residual risk of cardiovascular disease. The progress from PCSK9 discovery to the development of targeted treatment has been unprecedented in terms of scale and speed. The first suggestion of a link between PCSK9 and hypercholesterolemia was published in 2003; a decade later, two meta-analyses of clinical trials comparing anti-PCSK9 treatment to placebo or ezetimibe, including >10,000 hypercholesterolemic individuals, were published. Currently, three PCSK9 inhibitors are being evaluated in clinical outcome trials and the results will determine the future of these lipid-lowering therapies by establishing their clinical efficacy in terms of cardiovascular event reduction, safety, and the consequences of prolonged exposure to very low levels of LDL-cholesterol. Irrespective of their outcomes, the exceptionally rapid development of these drugs exemplifies how novel technologies, genetic validation, and rapid clinical progression provide the tools to expedite the development of new drugs.
Project description:There is a critical need for alternative, potent agents that can reduce low-density lipoprotein cholesterol (LDL-C) levels in patients with heterozygous familial hyperlipidemia and statin intolerance and those not reaching lipid-lowering treatment goals who are at high risk for cardiovascular (CV) events. The first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was approved in July 2015 by the US Food and Drug Administration as an adjunct to diet and maximally tolerated statin therapy for treatment of adults with heterozygous familial hyperlipidemia or clinical atherosclerotic CV disease, who require additional lowering of LDL-C levels. In clinical trials, PCSK9 inhibitors have been shown to reduce LDL-C levels by as much as 60% to 70% when administered as monotherapy or as an add-on treatment to statins and other lipid-lowering therapies. In studies of PCSK9 genetic mutations, loss of function in the PCSK9 allele was associated with a relative decrease of 88% in the risk for atherosclerotic CV events during 15 years of patient follow-up. The use of PCSK9 inhibitors may eventually support the LDL-C hypothesis that the lower the LDL-C level, the lower the CV risk. Although some recent clinical practice guidelines have deemphasized the importance of numeric LDL-C targets, many clinicians are reluctant to discard them, and this position is supported by recent clinical evidence. We eagerly await the results of the ODYSSEY, FOURIER, and SPIRE clinical outcome trials, which we anticipate will provide further validation that "lower is better" with respect to reducing LDL-C levels and improving clinical outcomes.