1,721,146 research outputs found
The new ACC/AHA guidelines on the treatment of dyslipidemia: cons.
Full text linkIn November 2013, the American College of Cardiology
(ACC) and the American Heart Association (AHA) published
a set of guidelines on the control of blood cholesterol
to reduce atherosclerotic cardiovascular disease (ASCVD)
risk in adults [1]. This latest set of ACC/AHA guidelines
focuses specifically on cholesterol management and on
statin therapy rather than other forms of dyslipidemias or
alternative therapeutic approaches (as in the ESC/EAS
2011 guidelines) and recognizes that more intensive statin
treatment is superior to less intensive treatment for many
patients. However, the shift away from the previous ATPIII
set of guidelines published a decade ago [2], which
provided a comprehensive guide to lipid management, has
created controversy and confusion about the relative merits
of these new ACC/AHA guidelines when compared with
existing guidelines such as the ESC/EAS guidelines for
‘the management of dyslipidemias [3]’. Whereas some
have embraced the new ACC/AHA guidelines as ‘a step in
the right direction’ for reasons of simplifying patient care,
others disagree; certainly sweeping endorsements are
overly optimistic and warrant greater cautio
Heterozygous familial hypercholesterolemia: the first challenge for anti-PCSK9 monoclonal antibodies
No full textHeterozygous familial hypercholesterolemia (HeFH) is characterized by a prevalence of 1/200 (higher than 1/500 as previously estimated): based on this updated prevalence, in Italy there are about 250-300 000 subjects with HeFH. Patients with HeFH are significantly underdiagnosed (in Italy only 4-5% of total estimated HeFH are properly diagnosed), undertreated (only 1 in 5 to 10 HeFH at target for LDL-cholesterol), and characterized by a high or very high cardiovascular risk. There are simple criteria for the diagnosis of familial hypercholesterolemia such as those issued by the Dutch Lipid Clinic Network (DLCN), easy to implement both in general practice as well as by the specialists. Genetic diagnosis is strongly suggested to support the diagnosis of familial hypercholesterolemia. Lipid-lowering therapy with high dose of highly effective statins, often associated with ezetimibe, should be initiated immediately at diagnosis in adults and at age 8-10 years in childhood. Evolocumab and alirocumab are monoclonal antibodies against PCSK9. They are a highly innovative lipid-lowering approach, characterized by a good safety profile and a remarkable LDL-cholesterol lowering effect when associated with the maximally tolerated dose of statins plus ezetimibe. Studies with alirocumab and evolocumab in HeFH patients show a further LDL-cholesterol decrease by 50-60% vs intensive lipid-lowering therapy with statins ± ezetimibe, with 70-80% of HeFH patients achieving their LDL-cholesterol targets
Reducing cholesterol levels to decrease cardiovascular events: The role of new proprotein convertase subtilisin/kexin type 9 inhibitors
Full text linkThe need for new drugs to treat severe hypercholesterolemia is relevant because there are patients with genetic defects of cholesterol metabolism in whom current therapies are not effective enough or because there are patients at high risk for cardiovascular events necessitating extremely ambitious cholesterol targets and, finally, because in some patients the standard therapy is not
well tolerated. Even under optimal therapeutic conditions, maximal therapy with statin also in association with a second lipid-lowering agent (ezetimibe, ionic exchange resin, fibrates etc.) may not be sufficient to reach the therapeutic target. This situation is evident in patients with familial hypercholesterolemia the prevalence of which was initially estimated in 1/500 patients for the heterozygous
form and 1/1000 000 for the homozygous form. More recent analyses, on a large population cohort, estimated the prevalence of the heterozygous form to be 1/200–300 and for the homozygous 1/300 000–400 000.1 Another group of patients in whom the therapeutic target could be difficult to reach are those intolerant to statins. The prevalence of this condition is about 5–10%.2
For all those patients, new classes of drugs are being introduced that are able to act through different mechanisms of action than statins.
New cholesterol-lowering drugs
Four new classes of drugs designed to reduce LDL cholesterol (LDL-C) levels are currently in advanced phase of study. In patients with high or very high cardiovascular risk, those drugs are currently utilized in association with currently available lipid-lowering agents. For the inhibitors of the protein proprotein convertase subtilisin/kexin type 9 (PCSK9), studies testing efficacy with
clinical cardiovascular endpoints are currently under way. Results of these trials should be available in 2–3 years. 1) A first drug is the antisense oligonucleotide, mipomersen acting by decreasing the hepatic synthesis of apolipoprotein B (ApoB) through degradation of its mRNA with a reduction of assembly and production of all atherogenic lipoproteins. In heterozygote patients for familial hypercholesterolemia, cardiovascular disease and on maximal statin treatment, mipomersen decreased LDL-C by 28%, Lp(a) by 21% and ApoB by 26%. Mipomersen has been approved only for treatment of patients with homozygous familial hypercholesterolemia by the Food and Drug Administration, because relevant side effects such as hepatic steatosis, inflammatory reactions at the site of injection and flu-like symptoms are commonly reported. 2) Lomitapide inhibits microsomal triglyceride transfer protein (MTP) impairing hepatic production and secretion of Very Low Density Lipoproteins (VLDL), MTP is the key protein in the transfer of triglycerides on the apoprotein B. In patients with homozygous familial hypercholesterolemia being treated with diet only, the maximum reduction with lomitapide was of 51% for LDL-C, 79% for VLDL cholesterol, 65% for triglycerides, 56% for ApoB and 15% for Lp(a); unfortunately, hepatic steatosis was frequent as well as gastrointestinal side effects. (3) The third class of drugs under investigation are the inhibitors of cholesterol ester transfer protein: anacetrapib reduces the exchange of cholesterol ester from HDL to ApoB lipoprotein (chilomicrons, VLDL and LDL), and the reverse transfer of triglycerides from ApoB-containing lipoproteins to HDL. Anacetrapib is the only drug in this class still under study; it can decrease LDL-C and Lp(a) by 40% if used in patients treated with statin and not affected by familial hypercholesterolemia, whereas it increases the HDL cholesterol by 140%. (4) A new very promising class of cholesterol-lowering drugs are the monoclonal antibodies against PCSK9. PCSK9 significantlymodulates the biologic cycle of the LDL receptors (LDLRs). This protein is synthesized and released by the hepatocytes (also by the intestine, the kidney and central nervous system), where it binds to the complex LDL–LDLR on the surface of the
hepatocytes. Once bound to the LDL–LDLR complex and internalized in the hepatocytes, it prevents the intracellular recycling of the LDLR favoring its degradation and thus reducing the number of receptor on the cellular membrane. The monoclonal antibody interacting with PCSK9 prevents its binding to the LDL–LDLR complex favoring the recycling (rather than the degradation) of the latter on the surface of the hepatocytes. This mechanism allows more LDLRs on the cellular surface to be available to bind lipoproteins. The monoclonal antibodies anti-PCSK9 reduce LDLC
by 60–70% and Lp(a) by 20–25% in heterozygous patients for familial hypercholesterolemia treated with statins
Linee guida per la gestione del rischio macrovascolare
No full textRIASSUNTO
La malattia cardiovascolare rimane la principale causa di mortalità ed invalidità nella nostra società.
• Un approccio efficace e multifattoriale alla riduzione del rischio di eventi cardiovascolari rappresenta una priorità nelle linee guida delle società scientifiche nazionali ed internazionali ed un’esigenza irrinunciabile dei sistemi socio-sanitari.
• La dislipidemia ed in particolare gli elevati livelli di LDL-C sono unanimemente considerati il fattore di rischio chiave per la malattia cardiovascolare.
• L’utilizzo della terapia con statine (quando indicato statina+ezetimibe) rappresenta l’approccio di 1° scelta per la riduzione del LDL-C e del rischio cardiovascolare
• I dati dei trials clinici più recenti hanno chiaramente messo in luce che anche con valori ottimali (a target) di LDL-C con statina, i pazienti con fattori di rischio cardiometabolici presentano un significativo rischio di eventi cardiovascolari: RISCHIO CARDIOVASCOLARE RESIDUO
• La mancata correzione dei persistenti livelli elevati di trigliceridi e/o dei ridotti livelli di HDL-C contribuiscono in modo rilevante al rischio cardiovascolare residuo in corso di terapia con statine
• Le più recenti Linee Guida suggeriscono, una volta raggiunti i livelli ottimali di LDL-C, di: 1) controllare se TG 40 mg/dl; 2) in caso di elevati TG e/o basso HDL-C apportare gli adeguati cambiamenti nello stile di vita e 3) prendere in considerazione l’associazione statina-fenofibrato o statina-acido nicotinico
• Il recente documento del Panel della Società Europea dell’Aterosclerosi (14) ritiene che tale approccio terapeutico sequenziale (riassunto nella flow-chart in Figura 8) può contribuire efficacemente alla riduzione del rischio cardiovascolare residuo che caratterizza attualmente i pazienti con fattori di rischio cardiometabolici
Non- high-density lipoprotein cholesterol and cardiovascular disease in patients with diabetic dyslipidaemia
Full text linkElevated levels of blood lipids are one of the major risk factors for cardiovascular (CV) disease in patients with type 2 diabetes mellitus. Diabetic dyslipidaemia is characterised by the presence of potentially atherogenic lipids, including high levels of plasma triglycerides (TGs), mild-to-moderately elevated levels of low-density lipoprotein cholesterol (LDL-C), and low levels of high-density lipoprotein cholesterol (HDL-C). Statin therapy to reduce LDL-C levels is the mainstay of treatment practice to reduce CV risk. However, despite achieving targets for LDL-C, patients with diabetic dyslipidaemia remain at a high risk of residual CV events. Hence there is a need to target other components (i.e. elevated TGs) of the atherogenic dyslipidaemia that are not affected by treatment with statins. This review highlights the clinical benefits of using non-HDL-C, a single marker that includes all atherogenic lipoproteins, as a leading treatment target to reduce the residual CV risk
Residual cardiovascular risk in secondary prevention.
No full textDespite substantial progress in the characterization and pharmacological treatment of risk factors associated with cardiovascular disease (CVD), residual cardiovascular risk represents a challenge to an effective CVD primary and secondary prevention. A multifactorial approach aimed at controlling all risk factors present in each individual patient is of paramount importance to effectively reduce the risk of CV events. While aggressive as compared to conventional LDL-cholesterol lowering provides further CV events reduction in secondary prevention patients, significant residual cardiovascular risk remains even after intensive statin therapy and an LDL-C levels of <70 mg/dL. Combination lipid-lowering strategies with a statin and fenofibrate or a statin and nicotinic acid may provide significant residual CV risk reduction in selected subgroups of patients (i.e. patients with diabetes on statin therapy and persistently low HDL-C and/or high triglycerides). Intensive risk factor management approaches aimed at controlling plasma LDL-C, glucose metabolism and blood pressure may significantly reduce residual CV risk; they should however be implemented based on individual cardiovascular risk profiles and clinical phenotypes, following the footsteps of personalized medicine
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