Summary The proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol metabolism mainly by targeting the low-density lipoprotein receptor (LDLR) for degradation in the liver. ...Gain-of-function mutations in PCSK9 are one of the genetic causes of autosomal dominant hypercholesterolaemia. Conversely, loss-of-function mutations are associated with lower concentrations of LDL cholesterol (LDL-C) and reduced coronary heart disease. As these loss-of-function mutations are not associated with apparent deleterious effects, PCSK9 inhibition is an attractive new strategy for lowering LDL-C concentration. Among the various approaches to PCSK9 inhibition, human data are only available for inhibition of PCSK9 binding to LDLR by monoclonal antibodies. In phase II studies, the two most advanced monoclonal antibodies in development (alirocumab and evolocumab) decreased atherogenic lipoproteins very effectively and were well tolerated. A dramatic decrease in LDL-C up to 70% can be obtained with the most efficacious doses. Efficacy has been evaluated so far in addition to statins in hypercholesterolaemic patients with or without familial hypercholesterolaemia, in patients with intolerance to statin therapy and in monotherapy. Large phase III programmes are ongoing to evaluate the long-term efficacy and safety of these very promising new agents.
Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are ...receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy.
We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24.
At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks. The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02).
Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY LONG TERM ClinicalTrials.gov number, NCT01507831.).
Regulation of triglyceride-rich lipoprotein (TGRL) metabolism. Serum triglyceride concentration identifies the presence of potentially atherogenic TGRLs. Human genetics strongly support remnants of ...TGRLs as a causal cardiovascular risk factor. Remnants of TGRLs play a role in residual risk on statin therapy. Apo: apolipoprotein; ANGPTL: angiopoietin-like protein; LPL: lipoprotein lipase; RLP: remnant lipoprotein.▪
Low-density lipoprotein cholesterol is a well-known causal factor for atherosclerotic cardiovascular disease, and is the primary target of lipid-lowering therapy. There is, however, still a substantial risk of atherosclerotic cardiovascular disease events despite intensive statin therapy, and data from clinical trials suggest that an elevated concentration of triglycerides is a marker of residual cardiovascular risk on low-density lipoprotein-lowering therapy. Serum triglycerides are a biomarker for triglyceride-rich lipoproteins, and several lines of evidence indicate that triglyceride-rich lipoproteins and their cholesterol-enriched remnant particles are associated with atherogenesis. Moreover, genetic data in humans strongly suggest that the remnants of triglyceride-rich lipoproteins are a causal cardiovascular risk factor. Although lifestyle changes remain the cornerstone of management of hypertriglyceridaemia, a recent trial with high doses of the omega-3 fatty acid icosapent ethyl showed a significant reduction in cardiovascular events that was not explained by the reduction in triglycerides alone. In patients with elevated triglycerides, several novel drugs are in development to reduce the residual risk on statin therapy linked to an excess of atherogenic triglyceride-rich lipoproteins. In this review, we provide an update on the biology, epidemiology and genetics of triglycerides, and the risk of atherosclerotic cardiovascular disease.
Le cholestérol des lipoprotéines de basse densité est un facteur causal bien reconnu des maladies cardiovasculaires liées à l’athérosclérose et c’est l’objectif primaire d’un traitement hypolipémiant. Toutefois un risque substantiel persiste malgré un traitement par statine de forte intensité et des données récentes d’essais cliniques suggèrent qu’une élévation des triglycérides est un marqueur du risque cardiovasculaire résiduel sous traitement abaissant les lipoprotéines de basse densité. Les triglycérides sériques sont un biomarqueur des lipoprotéines riches en triglycérides et de nombreuses preuves indiquent que les lipoprotéines riches en triglycérides et leurs résidus d’hydrolyse (ou remnants) enrichis en cholestérol participent à l’athérogénèse. De plus des études génétiques supportent fortement un rôle causal des remnants dans le risque cardiovasculaire. Bien que les mesures hygiéno-diététiques restent la pierre angulaire de la prise en charge d’une hypertriglycéridémie, une étude clinique récente utilisant de fortes doses d’un acide gras omega-3, l’icosapent ethyl, a montré une réduction significative des évènements cardiovasculaires, inexpliquée par la seule baisse des triglycérides. Chez des patients avec élévation des triglycérides sous traitement par statine, plusieurs nouvelles approches thérapeutiques sont en développement pour réduire le risque résiduel lié à l’excès de lipoprotéines riches en triglycérides. Cette revue propose une mise à jour des données biologiques, épidémiologiques et génétiques des relations entre triglycérides et risque de maladies cardiovasculaires liées à l’athérosclérose.
Mixed dyslipidemia is a common lipid disorder characterized by the presence of an atherogenic lipoprotein phenotype due to abnormalities in various atherogenic and anti-atherogenic lipoproteins. ...Despite the link between the decrease of LDL-cholesterol by statin treatment and the prevention of cardiovascular disease, a high residual risk is observed in statin trials. This residual risk is partly explained by lipoprotein abnormalities other than LDL. Fenofibrate exerts a favorable effect on the atherogenic lipid profile of mixed dyslipidemia and can effectively reduce cardiovascular disease in patients with mixed dyslipidemia. Fenofibrate may offer important treatment alternatives as a second-line therapy in several circumstances: in combination with a statin for patients with mixed dyslipidemias not at goals on statin mono-therapy; in monotherapy for patients intolerant or with contraindication to statin therapy; and in combination with other drugs (ezetimibe, colesevelam) for patients with mixed dyslipidemias, known intolerance, or contraindication to statin and not at goals on fenofibrate monotherapy. However, the role of fenofibrate-statin therapy and of other therapies involving fenofibrate in cardiovascular risk reduction strategies remains to be established.
Abstract Objective To compare lipid-lowering efficacy of adding alirocumab to rosuvastatin versus other treatment strategies (NCT01730053). Methods Patients receiving baseline rosuvastatin regimens ...(10 or 20 mg) were randomized to: add-on alirocumab 75 mg every-2-weeks (Q2W) (1-mL subcutaneous injection via pre-filled pen); add-on ezetimibe 10 mg/day; or double-dose rosuvastatin. Patients had cardiovascular disease (CVD) and low-density lipoprotein cholesterol (LDL–C) ≥70 mg/dL (1.8 mmol/L) or CVD risk factors and LDL–C ≥100 mg/dL (2.6 mmol/L). In the alirocumab group, dose was blindly increased at Week 12 to 150 mg Q2W (also 1-mL volume) in patients not achieving their LDL–C target. Primary endpoint was percent change in calculated LDL–C from baseline to 24 weeks (intent-to-treat). Results 305 patients were randomized. In the baseline rosuvastatin 10 mg group, significantly greater LDL–C reductions were observed with add-on alirocumab (−50.6%) versus ezetimibe (−14.4%; p < 0.0001) and double-dose rosuvastatin (−16.3%; p < 0.0001). In the baseline rosuvastatin 20 mg group, LDL–C reduction with add-on alirocumab was −36.3% compared with −11.0% with ezetimibe and −15.9% with double-dose rosuvastatin ( p = 0.0136 and 0.0453, respectively; pre-specified threshold for significance p < 0.0125). Overall, ∼80% alirocumab patients were maintained on 75 mg Q2W. Of alirocumab-treated patients, 84.9% and 66.7% in the baseline rosuvastatin 10 and 20 mg groups, respectively, achieved risk-based LDL–C targets. Treatment-emergent adverse events occurred in 56.3% of alirocumab patients versus 53.5% ezetimibe and 67.3% double-dose rosuvastatin (pooled data). Conclusions The addition of alirocumab to rosuvastatin provided incremental LDL–C lowering versus adding ezetimibe or doubling the rosuvastatin dose.
Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels that is associated ...with mutations in the genes LDLR (encoding low-density lipoprotein receptor) or APOB (encoding apolipoprotein B). We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH. PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis.
After the approval of alirocumab and evolocumab, the first two monoclonal antibodies (mAbs) targeting proprotein convertase subtilisin kexin type 9 (PCSK9), this review provides an update on recent ...PCSK9 inhibitors data and describes recommendations for the use before the results of the ongoing cardiovascular endpoint trials.
New studies and complementary analysis of phase III trials have consistently shown that alirocumab and evolocumab are highly effective in reducing LDL-cholesterol and to some extent lipoprotein (a). Some preliminary findings coming from exploratory and post-hoc analyses of the longer-term safety phase III trials and meta-analyses suggest that these mAbs can decrease the incidence of cardiovascular events. Whether or not mAbs targeting PCSK9 definitively reduce the incidence of cardiovascular events without safety concerns shall be demonstrated with the ongoing cardiovascular outcome trials. Waiting these outcome trials and given the high cost of these mAbs, groups of experts have proposed as priorities groups of patients with familial hypercholesterolemia and with atherosclerotic cardiovascular disease who have substantially elevated LDL-cholesterol on maximally tolerated statin/ezetimibe therapy.
Before the results of large cardiovascular outcome trials, PCSK9 inhibitors should be only used in some categories of patients with familial hypercholesterolemia and/or with atherosclerotic cardiovascular disease.
This online interactive survey investigated lipid-lowering approaches of French cardiologists in high- and very high-cardiovascular risk patients with hypercholesterolemia.
Physicians assessed three ...hypothetical patients at three clinic visits, and selected the patients' cardiovascular risk category, target low-density lipoprotein cholesterol (LDL-C) and treatment.
A total of 162 physicians completed 480 risk assessments; 58% of assessments correctly categorized the hypothetical patients. Most physicians chose the correct LDL-C target for one of the very high-risk patients, but higher-than-recommended targets were selected for the other very high-risk patient and the high-risk patient. Statins were the most commonly chosen treatment.
French cardiologists often underestimate cardiovascular risk in patients with hypercholesterolemia, select a higher-than-recommended LDL-C target and prescribe less intensive treatment than that recommended by guidelines.
Purpose
During the alirocumab open-label extension study ODYSSEY OLE (open-label extension; NCT01954394), physicians could adjust alirocumab dosing for enrolled patients, who were diagnosed with ...heterozygous familial hypercholesterolemia (HeFH) and who had completed previous phase III clinical trials with alirocumab. This post hoc analysis evaluated the differences in physician–patient dosing decisions between the regions of Western Europe, Eastern Europe, North America, and the rest of the world (ROW).
Methods
Patients (
n
= 909) who received starting dose alirocumab 75 mg every 2 weeks (Q2W) during ODYSSEY OLE (patients from FH I, FH II, and LONG TERM parent studies) were included. Low-density lipoprotein cholesterol (LDL-C) levels were blinded until week 8; subsequently, LDL-C values were communicated to physicians. From week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa, was possible.
Results
Mean LDL-C values used for the decision to increase dose from 75 to 150 mg Q2W were higher in Eastern Europe (3.7 mmol/L; 144.0 mg/dL) and ROW (3.8 mmol/L; 145.2 mg/dL) compared with Western Europe (3.1 mmol/L; 118.6 mg/dL) and North America (3.3 mmol/L; 126.6 mg/dL). Irrespective of region, the mean LDL-C at the time of decision to maintain at 75 mg Q2W was approximately 1.8 mmol/L (70 mg/dL). During ODYSSEY OLE (median treatment duration of 131.7 weeks), alirocumab was shown to have no unexpected long-term safety concerns.
Conclusions
In this OLE study, the observed variations in clinical treatment decisions suggest that physicians may perceive the severity of HeFH and/or the treatment of HeFH differently depending on their region.
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