RESUMO
BACKGROUND AND AIMS: Low-density lipoprotein cholesterol (LDL-C) is the main therapeutic target in the treatment of hypercholesterolemia. Small interfering RNA (siRNA) inclisiran is a new drug, which targets PCSK9 mRNA in the liver, reducing concentrations of circulating LDL-C. In randomized trials, inclisiran demonstrated a substantial reduction in LDL-C. The German Inclisiran Network (GIN) aims to evaluate LDL-C reductions in a real-world cohort of patients treated with inclisiran in Germany. METHODS: Patients who received inclisiran in 14 lipid clinics in Germany for elevated LDL-C levels between February 2021 and July 2022 were included in this analysis. We described baseline characteristics, individual LDL-C changes (%) and side effects in 153 patients 3 months (n = 153) and 9 months (n = 79) after inclisiran administration. RESULTS: Since all patients were referred to specialized lipid clinics, only one-third were on statin therapy due to statin intolerance. The median LDL-C reduction was 35.5% at 3 months and 26.5% at 9 months. In patients previously treated with PCSK9 antibody (PCSK9-mAb), LDL-C reductions were less effective than in PCSK9-mAb-naïve patients (23.6% vs. 41.1% at 3 months). Concomitant statin treatment was associated with more effective LDL-C lowering. There was a high interindividual variability in LDL-C changes from baseline. Altogether, inclisiran was well-tolerated, and side effects were rare (5.9%). CONCLUSION: In this real-world patient population referred to German lipid clinics for elevated LDL-C levels, inclisiran demonstrated a high interindividual variability in LDL-C reductions. Further research is warranted to elucidate reasons for the interindividual variability in drug efficacy.
Assuntos
Anticolesterolemiantes , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , LDL-Colesterol , Pró-Proteína Convertase 9 , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , RNA Interferente Pequeno/efeitos adversos , Anticolesterolemiantes/efeitos adversosRESUMO
Lipoprotein apheresis has been shown to improve the cardiovascular outcome in patients with atherosclerotic disease and therapy-refractory hypercholesterolemia or elevated lipoprotein (a) (Lp(a)). An elevated intake of omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has also been associated with a reduced cardiovascular risk. However, until now only little is known about the effect of apheresis treatment on the levels of omega-6 and omega-3 polyunsaturated fatty acids (n-6 PUFA and n-3 PUFA) in patients. Using gas chromatography (GC) the present study analyzed the content of n-6 and n-3 PUFA as well as saturated fatty acids and monounsaturated fatty acids in the plasma of 20 patients with hyperlipidemia undergoing regular lipoprotein apheresis procedures in direct pre- and post-therapy measurements. Lipoprotein apheresis uniformly reduced the concentrations of arachidonic acid (AA), EPA and DHA fatty acids analyzed in the plasma. However, the three different apheresis methods analyzed (heparin precipitation, membrane filtration and direct absorption) had different effects on the fatty acid profile in the plasma. We found that heparin precipitation and direct absorption apheresis procedures led to a significant decrease of plasma n-3 and n-6 PUFA by 40-50%. In contrast, patients undergoing membrane filtration apheresis, levels pre- and post-apheresis did not change significantly, with AA and EPA being only reduced by approximately 10% while levels of DHA were maintained pre- and post-apheresis. In contrast, total triglyceride levels were lowered most potently by membrane filtration apheresis. In summary, heparin precipitation and direct absorption apheresis approaches significantly lowered polyunsaturated fatty acids in plasma, while membrane filtration did not. This might have implications for cardiovascular and inflammatory risk/benefit profiles associated with n-6 and n-3 PUFA levels in the body.
Assuntos
Remoção de Componentes Sanguíneos/métodos , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-6/sangue , Hiperlipoproteinemias/terapia , Lipoproteínas/sangue , Absorção Fisico-Química , Adulto , Idoso , Biomarcadores/sangue , Remoção de Componentes Sanguíneos/instrumentação , Precipitação Química , Cromatografia Gasosa , Feminino , Filtração , Heparina/química , Humanos , Hiperlipoproteinemias/sangue , Hiperlipoproteinemias/diagnóstico , Masculino , Membranas Artificiais , Pessoa de Meia-Idade , Resultado do Tratamento , Triglicerídeos/sangueRESUMO
Severe hypertriglyceridemia is defined at a plasma triglyceride (TG) concentration of >885 mg/dl and may result - in particular when clinical symptoms appear before the age of 40 - from "large variant" mutations in genes which influence the function of the lipoprotein lipase (LPL). For diagnosis, secondary factors have to be excluded and treated before further genetic tests are considered. Typical symptoms in almost all patients are recurrent, sometimes severe abdominal pain attacks, which can result in acute pancreatitis, the most important, sometimes life-threatening complication. To minimize the risk of severe pancreatitis, the aim is to maintain the plasma TG concentration <1000 mg/dl. Other clinical manifestations which can occur and are reversible are eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, dyspnea syndrome, and impaired neurocognitive function. The hyperviscosity syndrome caused by chylomicronemia is seen as the underlying reason for some of the symptoms. Patients with mild-to-moderate hypertriglyceridemia have an increased cardiovascular risk. To lower this is the primary treatment goal here. Treatment mainly consists of a life-long, strict fat- and carbohydrate-restricted diet and the abstention from alcohol. Omega3-Fatty acids and fibrates can be used to lower plasma TG levels. Recently, new gene therapy approaches for LPL-deficient patients have become available in Germany.
Assuntos
Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/terapia , Doença Aguda , Doenças Cardiovasculares/etiologia , Alemanha , Humanos , Hipertrigliceridemia/genética , Lipase Lipoproteica/fisiologia , Pancreatite/etiologia , Fatores de Risco , Triglicerídeos/sangueRESUMO
Lipoprotein apheresis such as heparin-induced extracorporal LowDensityLipoprotein (LDL) Cholesterol precipitation (HELP) reduces apolipoprotein B-containing lipoproteins, most importantly low-density-lipoprotein (LDL), and lipoprotein (a) [Lp(a)]. It is used in patients with atherosclerotic disease and therapy-refractory hypercholesterolemia or progressive atherosclerotic disease in patients with elevated Lp(a). While lipid-lowering effects of lipoprotein apheresis are well-established, there are only sparse data regarding the effect of apheresis on individual omega-6 and omega-3 polyunsaturated fatty acids (n-6 PUFA and n-3 PUFA), such as arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which could increase (AA) or decrease (EPA and DHA) cardiovascular risk. Here we analyzed different omega-6 and omega-3 fatty acids in the blood of patients undergoing a single HELP apheresis procedure using gas chromatography (GC). Furthermore, we assessed the effect of HELP treatment on formation of lipid metabolites and mediators arising from these polyunsaturated fatty acids in the plasma by LC/ESI-MS/MS. Lipoprotein apheresis reduced the concentrations of fatty acids analyzed in the plasma by 40-50%. This was similar for AA, EPA and DHA. The reduction in fatty acid plasma levels was similar to the reduction of total triglycerides. However there was a trend towards an increase of PUFA metabolites associated with platelet activation, such as 12-hydroxyeicosatetraenoic acid (12-HETE) and 14-hydroxydocosahexaenoic acid (14-HDHA). These data indicate that HELP apheresis could interfere with achieving higher levels of n-3 PUFA in the plasma. Lipid apheresis treatment might also increase the formation of potentially pro- as well as anti-inflammatory lipid mediators derived from AA or EPA and DHA.
Assuntos
Remoção de Componentes Sanguíneos , Ácidos Graxos/sangue , Lipídeos/química , Lipoproteínas/química , Triglicerídeos/química , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Adulto , Idoso , Ácidos Docosa-Hexaenoicos/metabolismo , Eritrócitos/metabolismo , Humanos , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Oxilipinas/química , Plasmócitos/metabolismo , Fatores de RiscoRESUMO
Objective. To investigate the association of lipoprotein(a) and atherosclerosis-related autoimmune diseases, to provide information on possible pathophysiologic mechanisms, and to give recommendations for Lp(a) determination and therapeutic options. Methods. We performed a systematic review of English language citations referring to the keywords "Lp(a)" AND "autoimmune disease" AND "atherosclerosis," "Lp(a)" AND "immune system" OR "antiphospholipid (Hughes) syndrome (APS)" OR "rheumatoid arthritis" OR "Sjögren's syndrome" OR "systemic lupus erythematosus" OR "systemic sclerosis" OR "systemic vasculitis" published between 1991 and 2011 using Medline database. Results. 22 out of 65 found articles were identified as relevant. Lp(a) association was highest in rheumatoid arthritis (RA), followed by systemic lupus erythematosus (SLE), moderate in APS and lowest in systemic sclerosis (SSc). There was no association found between Lp(a) and systemic vasculitis or Sjögren's syndrome. Conclusion. Immune reactions are highly relevant in the pathophysiology of atherosclerosis, and patients with specific autoimmune diseases are at high risk for CVD. Elevated Lp(a) is an important risk factor for premature atherosclerosis and high Lp(a) levels are also associated with autoimmune diseases. Anti-Lp(a)-antibodies might be a possible explanation. Therapeutic approaches thus far include niacin, Lp(a)-apheresis, farnesoid x-receptor-agonists, and CETP-inhibitors being currently under investigation.
RESUMO
Lipoprotein(a) (Lp(a)) is a risk factor for premature coronary artery disease. Lp(a) levels can neither be influenced sufficiently by standard hypolipemic diet nor by drug therapy. Currently, lipid apheresis is the only option to effectively lower Lp(a) levels in patients with elevated Lp(a) and progressive CVD. The lipid-clinic at the Charité University hospital Berlin and other German apheresis centres have longstanding positive experience with this therapeutic regimen. Lately, in Germany lipid apheresis was accepted as the treatment of choice for patients with elevated Lp(a) levels > 60 mg/dl and progressive CVD. At the same time, care providers were obliged to conduct a controlled trial to prove the efficacy of lipid apheresis for this indication. Therefore, we designed a prospective, randomized, controlled trial to prove the hypothesis that lipid apheresis decreases vascular events.
Assuntos
Remoção de Componentes Sanguíneos , Doenças Cardiovasculares/prevenção & controle , Hiperlipidemias/tratamento farmacológico , Lipoproteína(a)/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Medicina Baseada em Evidências , Alemanha , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/complicações , Hiperlipidemias/mortalidade , Estudos Prospectivos , Resultado do Tratamento , Regulação para CimaRESUMO
BACKGROUND: Substantial residual cardiovascular risk persists despite effective LDL lowering treatment in populations at elevated risk for adverse cardiovascular outcomes. Low HDL cholesterol is an independent cardiovascular risk factor and occurs in about one-third of patients treated for dyslipidaemia in Europe. Moreover, randomised intervention studies have shown that increasing HDL cholesterol improves cardiovascular outcomes. Correcting low HDL cholesterol therefore presents a rational and proven strategy for intervention to produce further reductions in cardiovascular risk beyond those possible with a statin alone. Nicotinic acid (niacin in the USA) is the most effective agent currently available for increasing levels of HDL cholesterol. OVERALL STUDY RESULTS: A once-daily, prolonged-release formulation of nicotinic acid (Niaspan) is as effective on HDL cholesterol as the immediate-release formulation, and is equally effective at increasing HDL cholesterol whether or not patients are already taking a statin. Niaspan also shares the antiatherogenic benefit of nicotinic acid, and induced regression of atherosclerosis in patients with cardiovascular disease during a period of treatment of up to 2 years. The incidence of flushing, the principal side effect of nicotinic acid, is lower with Niaspan than with immediate-release nicotinic acid. Simple practical measures are available to minimise the incidence and impact of flushing, including careful dose titration and avoiding hot or spicy foods near the time of ingestion of Niaspan. The potential for hepatotoxicity, muscle toxicity or marked exacerbation of hyperglycaemia in diabetes with Niaspan is very low, with or without concomitant statin treatment. CONCLUSION: Niaspan provides a practical means of delivering the cardioprotective benefits associated with correction of low HDL cholesterol.
Assuntos
Doenças Cardiovasculares/prevenção & controle , HDL-Colesterol/metabolismo , Dislipidemias/tratamento farmacológico , Niacina/uso terapêutico , HDL-Colesterol/efeitos dos fármacos , Preparações de Ação Retardada , Dislipidemias/complicações , Rubor/induzido quimicamente , Humanos , Hipolipemiantes/efeitos adversos , Niacina/efeitos adversos , Resultado do TratamentoAssuntos
Anticolesterolemiantes/administração & dosagem , HDL-Colesterol/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Niacina/administração & dosagem , Sistemas de Notificação de Reações Adversas a Medicamentos , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Preparações de Ação Retardada , Esquema de Medicação , Alemanha , Humanos , Hipercolesterolemia/sangue , Estudos Multicêntricos como Assunto , Niacina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
OBJECTIVE: The main objective was to evaluate the safety and tolerability of prolonged-release nicotinic acid (niacin; Niaspan) in an usual care setting with patients receiving treatment for dyslipidaemia in Germany: the multiceNtre, open, uncontrolled sAfety and tolerability stUdy of a modified-release nicoTinic acId formuLation in sUbjects with dySlipidaemia and low HDL-cholesterol (NAUTILUS). RESEARCH DESIGN AND METHODS: This was a multicentre, open-label, 15-week study. Eligible patients had a diagnosis of dyslipidaemia with lipids inadequately controlled by 4 weeks of diet treatment. Additionally, patients had low HDL-cholesterol (< 1.03 mmol/L [< 40 mg/dL]) in men and < 1.29 mmol/L [< 50 mg/dL] in women), and had triglycerides < 9.03 mmol/L (< 800 mg/dL). Exclusion criteria included uncontrolled diabetes (HbA(1C) > 9%), significant hepatic, vascular or renal disease. The target dose was 2000 mg once daily. MAIN OUTCOME MEASURES: The main objective was to evaluate the safety and tolerability of prolonged-release nicotinic acid [incidence of adverse events (AE) and serious AE] in the overall population (the safety population). Efficacy parameters (lipid parameters) were also measured in the intent-to-treat population. RESULTS: A total of 566 patients were recruited, mostly with metabolic syndrome (39.4%), mixed hypercholesterolaemia (31.6%), isolated low HDL-cholesterol and markedly elevated cardiovascular risk for other reasons (10.8%), and primary hypercholesterolaemia (8.8%), according to NCEP/ATP III guidelines. The target dose was achieved by 65% of patients. Flushing was the most common side-effect (42%), as expected, and 9.7% withdrew for flushing. Other drug-related AEs occurred at low frequency (18.6%), and 8.7% withdrew for an AE other than flushing. Most AEs were mild or moderate in severity. Serious AEs considered possibly related to treatment occurred in three patients (0.5%); all resolved following treatment withdrawal. There was no hepatotoxicity or serious muscle AE. CONCLUSIONS: Prolonged-release nicotinic acid was well tolerated, and these results support its use in the management of patients at elevated cardiovascular risk due to low HDL-cholesterol.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hipolipemiantes/administração & dosagem , Niacina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Preparações de Ação Retardada , Avaliação de Medicamentos , Dislipidemias/tratamento farmacológico , Feminino , Alemanha , Humanos , Hipolipemiantes/efeitos adversos , Hipolipemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Niacina/efeitos adversos , Niacina/uso terapêuticoRESUMO
INTRODUCTION: Sudden sensorineural hearing loss (SSHL) is thought to be of various origins. Disturbances of microcirculation, autoimmune pathology and viral infection are among the most likely causes. Acute reduction of plasma fibrinogen and serum LDL positively influences hemorheology and endothelial function and might thus be an effective therapy for SSHL. OBJECTIVE: To test the hypothesis that fibrinogen/LDL-apheresis is as effective or superior to conventional therapy with plasma expanders and prednisolone in the treatment of SSHL. DESIGN: controlled, prospective, randomized, multicenter trial. SETTING AND PATIENTS: 201 patients were recruited from 01/2000 to 6/2001 at the University Clinics of Munich, Berlin, Hamburg and Bochum. Inclusion criteria was sudden sensorineural hearing loss of unknown origin within 6 days of onset. INTERVENTIONS: Single fibrinogen/ LDL-apheresis infusion of prednisolone (250 mg, tapered by 25 mg daily), hydroxyethyl starch (500 ml, 6%) and pentoxifylin (400 mg/day). MAIN OUTCOMES: Improvement of pure tone thresholds 48 h after onset of therapy. RESULTS: Over all improvement of pure tone thresholds in the fibrinogen/ LDL-apheresis treated patients is slightly but not significantly better than in the standard therapy group. After 48 h, 50% speech perception in the fibrinogen/ LDL-apheresis group (21.6+/-20.1 dB) is significantly (p<0.034) better than in the standard group (29.3+/-29.4 dB). Patients with plasma fibrinogen levels of more than 295 mg/dl have a substantial and significantly (p<0.005) better improvement of speech perception (15.3+/-17.3 dB) than standard treated patients (6.1+/-10.4 dB). CONCLUSIONS: Fibrinogen/LDLapheresis is at least equally effective compared to prednisolone treatment in sudden hearing loss. Selected patients with plasma fibrinogen of more than 295 mg/dl improve significantly better when treated with fibrinogen/LDLapheresis.
Assuntos
Remoção de Componentes Sanguíneos/métodos , Circulação Extracorpórea/métodos , Fibrinogênio/isolamento & purificação , Perda Auditiva Súbita/diagnóstico , Perda Auditiva Súbita/terapia , Heparina/uso terapêutico , Lipoproteínas LDL/isolamento & purificação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Precipitação Química , Feminino , Seguimentos , Perda Auditiva Súbita/tratamento farmacológico , Humanos , Lipoproteínas LDL/sangue , Masculino , Pessoa de Meia-Idade , Prednisolona , Estudos Prospectivos , Resultado do TratamentoRESUMO
A 50-year old male patient with familial hypercholesterolemia and hyperlipoproteinemia (a), who underwent low density lipoprotein-apheresis treatment developed heparin-induced thrombocytopenia type II (HIT II). Because heparin is contraindicated in patients with HIT, an alternative LDL-apheresis system and modified anticoagulation regimen was necessary. Treatment was changed to a new system called DALI (direct adsorption of lipids). After confirmation of the diagnosis HIT II, DALI LDL-apheresis was carried out with recombinant-hirudin (lepirudin) and citrate in order to prevent hypercoagulability. Efficient LDL-apheresis therapy with minimum therapeutic blood levels of lepirudin (1.4 mg/dl) was achieved with an initial intravenous bolus of 0.114 mg/kg of lepirudin followed by continuous lepirudin infusion of 0.350 mg/h. Thrombin-antithrombin III complex production was well controlled and other hemostatic markers showed no abnormalities. LDL-cholesterol and lipoprotein(a) concentrations were effectively reduced. R-hirudin offers a novel anticoagulation strategy and is, at present, the only alternative for patients with HIT II requiring LDL-apheresis on a regular basis.