Toward an international consensus-Integrating lipoprotein apheresis and new lipid-lowering drugs

Background: Despite advances in pharmacotherapy of lipid disorders, many dyslipidemic patients do not attain sufficient lipid lowering to mitigate risk of atherosclerotic cardiovascular disease. Several classes of novel lipid-lowering agents are being evaluated to reduce atherosclerotic cardiovascular disease risk. Lipoprotein apheresis (LA) is effective in acutely lowering the plasma concentrations of atherogenic lipoproteins including low-density lipoprotein cholesterol and lipoprotein(a), and novel lipid-lowering drugs may dampen the lipid rebound effect of LA, with the possibility that LA frequency may be decreased, in some cases even be discontinued. Sources of material: This document builds on current American Society for Apheresis guidelines and, for the first time, makes recommendations from summarized data of the emerging lipid-lowering drug classes (inhibitors of proprotein convertase subtilisin/kexin type 9 or microsomal triglyceride transfer protein, high-density lipoprotein mimetic), including the available evidence on combination therapy with LA with respect to the management of patients with dyslipidemia. Abstract of findings: Recommendations for different indications are given based on the latest evidence. However, except for lomitapide in homozygous familial hypercholesterolemia and alirocumab/evolocumab in heterozygous familial hypercholesterolemia subjects, limited data are available on the effectiveness and safety of combination therapy. More studies on combining LA with novel lipid-lowering drugs are needed. Conclusion: Novel lipid-lowering agents have potential to improve the performance of LA, but more evidence is needed. The Multidisciplinary International Group for Hemapheresis TherapY and Metabolic DIsturbances Contrast scientific society aims to establish an international registry of clinical experience on LA combination therapy to expand the evidence on this treatment in individuals at high cardiovascular disease risk

Low density lipoprotein apheresis

Lipid-apheresis (LA) and LDL-apheresis (LDLa) are extracorporeal techniques which permit the unselective or specific removal of lipids and lipoproteins, namely Low Density Lipoproteins (LDL), as well as other apolipoprotein B100 (apoB)-containing lipoproteins from plasma -Intermediate Density Lipoproteins, Lipoprotein(a)- [IDL, Lp(a)]. LDLa represents a selective upgrading (with both clinical and metabolic advantages) from conventional forms of extracorporeal therapy such as plasma-exchange (PEX) used in the seventies to treat severe hypercholesterolaemia. The primary reason to use LDLa is the treatment of homo-, double- (compound), and heterozygous familial hypercholesterolaemia (Hoz- DHtz- Htz FH). This technique also been shown efficacious in the treatment of other severe forms of hyperlipoproteinemia such as Autosomal Recessive Familial Hypercholesterolaemia, HyperLp(a)lipoproteinemia, Familial Combined Hyperlipoproteinemia, and other lipid metabolism disturbances associated with an elevated cardiovascular risk (CVR) when used on patients who are poor- or non-responders to pharmacological treatment following specific guidelines for the reduction of cholesterol in plasma. Patients with these severe forms of dyslipidemia and, particularly, those affected by FH are subject to coronary ischemic events and thus require an intensive, efficacious, constant, continuous, and personalized form of therapy. A therapy based solely on pharmacological drugs does not achieve the desired results in the Hoz- and DHtz forms of FH as well as in approximately 15-20% of the Htz form. In the aforementioned clinical conditions LDLa treatment offers a necessary therapeutic approach. LDLa can also be applied in the prevention of secondary recurrence of coronary ischemic events and of arterial stenosis which can appear rather frequently post-vascular surgery (coronary by-pass, percutaneous transluminal angioplasty). Emerging indications, the effects of LDLa on inflammatory parameters, and the future role of LDLa with regard to the novel potent lipid-lowering drugs are under investigation

Severe hypertriglyceridemia-related acute pancreatitis: Myth or reality?

[No abstract available

Lipid and low-density-lipoprotein apheresis. Effects on plasma inflammatory profile and on cytokine pattern in patients with severe dyslipidemia

Available evidence on the effects of therapeutic plasmapheresis (TP) techniques and in particular lipid-and LDL-apheresis (LDL-a) on plasmatic inflammatory mediators including cytokines were reviewed. Studies on this issue are not numerous. However, the review of existing evidence clearly suggests an active role of apheresis on the profile of inflammatory molecules and on cytokine pattern in plasma. These non-lipid-lowering effects can be defined to some extent pleiotropic or pleiotropic-equivalent. Although further studies are desirable, the data reported in this review confirm that lipid- and LDL-a not only show acute lipid-lowering and cholesterol-lowering effects, but also efficacy in reducing several proinflammatory peptides, including cytokines. This effect was not related apparently to lipids and lipoproteins reduction. Thus, TP (lipid- and LDL-a), commonly utilized in the treatment of severe genetically determined lipid disorders, unresponsive to hypolipidemic drugs, offers new possibilities of interpretation of its role in the mechanisms leading to the blockade of atherosclerotic lesion development and progression. The ability of TP on short-term to induce such a profound change in the plasmatic metabolic and inflammatory profiles must be kept in mind in the treatment of acute coronary syndromes, before and after interventions of coronary revascularization, and in the acute phase of cerebrovascular ischemia, at least in patients with severe dyslipidemia. Further studies are needed, in particular aimed at assessing if circulating cytokines may be downregulated by TP not only by direct removal, but through indirect effects on both gene translation and transcription perhaps via the cytokine receptor function. (C) 2011 Elsevier Ltd. All rights reserved

Severe Hypertriglyceridemia-Related Acute Pancreatitis

Acute pancreatitis is a potentially life-threatening complication of severe hypertriglyceridemia. In some cases, inborn errors of metabolism such as lipoprotein lipase deficiency, apoprotein C-II deficiency, and familial hypertriglyceridemia have been reported as causes of severe hypertriglyceridemia. More often, severe hypertriglyceridemia describes various clinical conditions characterized by high plasma levels of triglycerides (>1000mg/dL), chylomicron remnants, or intermediate density lipoprotein like particles, and/or chylomicrons. International guidelines on the management of acute pancreatitis are currently available. Standard therapeutic measures are based on the use of lipid-lowering agents (fenofibrate, gemfibrozil, niacin, -3 fatty acids), low molecular weight heparin, and insulin in diabetic patients. However, when standard medical therapies have failed, non-pharmacological approaches based upon the removal of triglycerides with therapeutic plasma exchange can also provide benefit to patients with severe hypertriglyceridemia and acute pancreatitis. Plasma exchange could be very helpful in reducing triglycerides levels during the acute phase of hyperlipidemic pancreatitis, and in the prevention of recurrence. The current evidence on management of acute pancreatitis and severe hypertriglyceridemia, focusing on symptoms, treatment and potential complications is reviewed herein

New clinical perspectives of hypolipidemic drug therapy in severe hypercholesterolemia

Patients with homozygous familial hypercholesterolemia (HoFH) represent the most severe patients within the spectrum of dyslipidemias. Untreated LDL-Cholesterol (LDL-C) levels in these patients are usually in the range 500 to 1200 mg/dL. Moreover, these patients exhibit a scarce responsiveness or even nonresponsiveness to oral lipid lowering agents. Patients with heterozygous familial hypercholesterolemia (HetFH) tend to have untreated LDL-C levels of 250-500 mg/dL. Many of these patients are responsive to HMGCoA-reductase inhibitors (statins) and/or other specific drugs. Unfortunately, a significant subset of these patients (5-10%) have a severe and/or refractory form of HetFH and after current maximal oral therapy, they remain significantly far from treatment goals (NCEP ATPIII guidelines). This would be defined as LDL-C levels of ≥ 190 mg/dL (prior CAD or CAD equivalent) or ≥ 250 mg/dL (no prior CAD or CAD risk-equivalent). The only current therapy option for these patients is Low Density Lipoproteins-apheresis (LDL_a). While LDL_a is very effective in reducing LDL-C, many patients do not receive this extracorporeal therapy because of costs and limited availability of LDL_a centers. Recently, new potent lipid-lowering drugs have been developed and are currently under investigation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role controlling the levels of LDL-C. Studies have demonstrated that PCSK9 acts mainly by enhancing degradation of the LDL receptor (LDLR) protein in the liver. Inactivation of PCSK9 in mice reduces plasma cholesterol levels. Since the loss of a functional PCSK9 in human is not associated with apparent deleterious effects, this protease is becoming an attractive target for lowering plasma LDL-C levels either alone or in combination with statins. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL-C showed to be an effective therapy to reduce LDL-C concentrations in patients with HozFH who are already receiving lipid-lowering drugs, including high-dose statins. Lomitapide is a potent inhibitor of microsomal triglyceride transfer protein and is highly efficacious in reducing LDL-C and triglycerides. Lomitapide is currently being developed for patients with HozFH at doses up to 60 mg/d. These new powerful lipid-lowering drugs might be possibly superior than available hypolipidemic agents. Their mechanisms of action, effectiveness, safety, and indication in severe, genetically determined dyslipidemias, are reviewed

[LDL apheresis: an update and overview. LDL apheresis in Sardinia, Italy (SMILDLa)]. [LDL-aferesi: aggiornamenti e stato dell'arte. Studio Multicentrico Italiano LDL-Aferesi (SMILDLa).]

LDL apheresis (LDLa) is an invasive therapeutic tool to control qualitative and quantitative disorders of lipid metabolism. It is aimed at achieving a metabolic balance in association with lipid-lowering drugs in patients with severe, genetically determined or acquired dyslipidemia who do not reach clinically adequate LDL-cholesterol (LDL-C) levels (<70 mg/dL) despite appropriate lipid-lowering drug treatment. A poorly known dyslipidemia is constituted by elevation of lipoprotein (a) [Lp(a)], which appears to be genetically determined and not influenced by diet or lipid-lowering medication. An Lp(a) level exceeding 30 mg/dL is an independent risk factor for premature cardiovascular disease and cerebrovascular disease. Numerous data support the notion that cardiovascular risk reduction is related to the degree of reduction of LDL-C, and the progression of atherosclerosis can be delayed or reversed by intensive and continuous cholesterol-lowering treatment. After the introduction of HMG-CoA reductase inhibitors (statins), the clinical benefit of cholesterol-lowering treatment has received significant confirmation. However, this treatment has shown poor results in the most severe, genetically determined forms. LDLa is an intensive extracorporeal cholesterol-lowering treatment approach with well documented efficacy and safety. It has also shown effects not directly correlated with its lipid-lowering activity, such as antioxidant effects on oxidized LDL and antiinflammatory effects on the cytokine network, the endothelium and the coagulation system. Finally, data acquired by the Italian Multicenter Study on LDLa Working Group were highlighted and the new evidence in the literature discussed

LDL aferesi: stato dell’arte

Nella rassegna si riportano elementi inerenti la Lipidoaferesi e la LDL aferesi (LA, LDL_a). Sono descrittein breve le tecniche, nella loro evoluzione nelle ultime tre decadi, del resto già ampiamente elucidatein letteratura. Le indicazioni consolidate, il trattamento e le nuove possibili indicazioni emergenti,sono illustrate più ampiamente. In particolare, si riportano le evidenze di letteratura sull’uso della LAe della LDL_a nella Ipercolesterolemia Familiare (IF), nella Restenosi, nella Glomerulosclerosi Focale,nell’Arteriosclerosi Obliterante, nella Sudden Hearing Loss, nella Maculopatia Degenerativa Senile,nella Sepsi, nel post Trapianto Cardiaco e nello Stroke. Si descrivono in sintesi il progetto ed i risultatidello Studio Multicentrico Italiano per la LDL_a, che ha condotto nel 2009 alla II Consensus ConferenceItaliana sulla LDL_a. Uno spazio più ampio è dedicato agli effetti delle tecniche di LA ed LDL_a sugliendpoints cardiovascolari e sulla progressione e regressione dell’arteriosclerosi. La LDL_a pediatricaviene illustrata nelle sue più recenti evidenze. Infine, si conferisce una trattazione ampia e dettagliatasugli effetti lipid-unrelated della LDL_a, cioè quelli cd. pleiotropici e pleiotropici-equivalenti, con particolareriguardo per gli effetti sulla protezione vascolare e sui peptidi mediatori dell’infiammazione.Su questi ultimi sono riportate le evidenze più recenti della letteratura. Infine, vengono brevementeesposti i farmaci ipolipemizzanti di più recente introduzione, con un particolare interesse verso future,promettenti nuove molecole ancora in fase di sperimentazione

La prevenzione ed il trattamento dei fattori di rischio per la malattia cardiovascolare nella donna in pre e postmenopausa: linee guida a confronto

Le linee guida elaborate nel 2011 dalle società di cardiologia americane (American Heart Association: AHA) ed europee (European Atherosclerosis Society: EAS; European Society of Cardiology: ESC) hanno centrato in modo specifico il profilo di rischio e gli interve ti di prevenzione dedicati alla donna. Queste indicazioni riconoscono, da un lato, la scarsa presenza femminile negli studi sul rischio cardiovascolare (RCV) e dall’altro l’evidenza di alcune differenze tra peso relativo dei fattori di rischio, stima del rischio cardiovascolare totale, ed efficacia dei differenti interventi tra uomo e donna. Inoltre, nella valutazione del profilo di rischio vengono inserite nuove variabili legate alla funzione riproduttiva ed in particolare alla storia di gravidanze patologiche (ipertensione in gravidanza, preeclampsia, diabete gestazionale). La donna presenta a 60 anni il rischio che l’uomo presenta 10 anni prima, e quindi l’età media della menopausa, intorno ai 50 anni, rappresenta un momento critico di valutazione e l’occasione per incoraggiare ad adottare misure di prevenzione primaria. Le linee guida dell’AHA ed EAS/ESC concordemente riportano gli interventi utili di prevenzione e di terapia per la salute cardiovascolare nella donna e tra questi esprimono un parere negativo sulla utilizzazione della terapia ormonale sostitutiva in menopausa. Specularmente, le società di ginecologia hanno discusso la mole di evidenze sul ruolo della terapia ormonale cercando di conciliare i risultati degli studi epidemiologici e producendo delle nuove linee guida sull’uso della terapia in menopausa. Dal confronto delle linee guida emerge dunque il potenziale ruolo della figura del ginecologo nell’ambito del RCV della donna: identificare precocemente il soggetto a rischio, incoraggiare l’aderenza a misure di prevenzione comprendenti sia il corretto stile di vita che l’uso di farmaci e/o procedure mirate, discutere i rischi ed i benefici in base ai quali consigliare alla donna sintomatica una adeguata terapia ormonale all’inizio della menopausa