Publications by authors named "Eric Bruckert"

202 Publications

Patient characteristics, treatment patterns, and adherence to lipid-lowering therapies following an acute coronary syndrome.

Rev Cardiovasc Med 2020 Dec;21(4):643-650

Health Economics and Outcomes Research, Amgen GmbH, 6343, Rotkreuz, Switzerland.

Despite dyslipidaemia management guidelines, many patients do not reach low-density lipoprotein cholesterol targets due to insufficiently intensive regimens or lack of adherence to their medication. This was a retrospective cohort study on the Pharmacoepidemiologic General Research eXtension (PGRx)-acute coronary syndrome (ACS) registry. Patients included were ≥ 18 years old who suffered an ACS between 2013 and 2016, and treated with lipid-lowering therapy (LLT) at hospital discharge or within 92 days. Patients were followed up to 12 months' post index ACS, a new cardiovascular event, loss to follow-up or death. Treatment intensity (high, moderate and low intensity statins ± ezetimibe) and adherence (proportion of days covered > 80%) are described. A total of 2,695 patients were included; mean age [SD] was 63.1 [12.8] years, and 77% were men. High, moderate and low intensity statins were started in 56% (1,520), 36% (971), and 3% (86) of patients, respectively. A further 2% (46) were on statin/ezetimibe combination, 2% (42) on other LLT and 1% (30) on ezetimibe alone. At follow-up, around 70% of patients were adherent to LLT, with those on moderate intensity treatments showing better adherence (76%) than those on low (63%) or high (67%) intensity treatments. Despite guideline recommendations, many patients following an ACS are not treated with high intensity statins, and adherence remains far from optimal. Effort should be made to increase the proportion of patients treated with high intensity statins following an ACS and to further improve treatment adherence.
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http://dx.doi.org/10.31083/j.rcm.2020.04.189DOI Listing
December 2020

Prevalence and management of hypercholesterolemia in France, the Esteban observational study.

Medicine (Baltimore) 2020 Dec;99(50):e23445

French Public Health Agency, Saint-Maurice.

Hypercholesterolemia is a major risk factor for cardiovascular diseases. However, its management in everyday clinical practice is often suboptimal. The aims of the Esteban study were to estimate the prevalence of hypercholesterolemia and to describe its management in France in 2015.Esteban is a cross-sectional, publicly funded survey, representative of the French population. Data were collected using questionnaires and biological and clinical examinations in 3021 adults aged 18-74.The lipid-lowering treatments were obtained by matching the individual data of the subjects included in the Esteban survey with data from the Système national de données de santé. Hypercholesterolemia was defined as either a low density lipoprotein cholesterol value higher than the goal set in the European Society of Cardiology/European Atherosclerosis Society guidelines as a function of individual cardiovascular risk level, or at least 1 delivery of lipid-lowering treatment. Adherence was defined by the proportion of days covered by the lipid-lowering treatment in the 6 months preceding clinical examination. Prevalence of hypercholesterolemia in France was 23.3% (27.8% in men, 19.0% in women). Mean low density lipoprotein cholesterol was 3.38 mmol/l in French participants. Among them, 7.2% were treated (8.5% of men, 5.8% of women), while 16.1% of adults went untreated (19.3% of men, 13.2% of women). Only 29.7% of secondary prevention adults had a delivery of lipid-lowering treatments in the 6 months preceding clinical examination. Fewer than 1 in 3 treated adults were adherent, i.e. more than 80% of days covered by a treatment. This proportion reached 37.4% in the high-risk group, with no significant difference of adherence in people with or without a personal history of cardiovascular disease in this group.This study showed that hypercholesterolemia is a common metabolic disease in France, affecting 23.3% of the population. Lipid-lowering prescriptions diverged greatly from current recommendations, with less than a third of eligible patients being treated.
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http://dx.doi.org/10.1097/MD.0000000000023445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738064PMC
December 2020

Advances in the management of statin myopathy.

Curr Opin Endocrinol Diabetes Obes 2021 Apr;28(2):142-151

Department of Endocrinology and Cardiovascular Disease Prevention, Assistance Publique-Hôpitaux de Paris, La Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.

Purpose Of Review: Statins are highly effective therapies for reducing low-density lipoprotein cholesterol and preventing cardiovascular events. However, many patients taking statins experience statin-associated muscle symptoms. In the current manuscript, we review algorithms to define statin intolerance and approaches to optimize cardiovascular risk reduction and reduce the nocebo effect among individuals reporting statin-associated muscle pain.

Recent Findings: Patients with statin intolerance have a higher cardiovascular event risk. These data underscore the need to apply clinical strategies that improve treatment utilization and adherence of patients experiencing statin-related side effects. Recent data have shown that the nocebo effect is frequent with statin therapy. This may be explained by the high frequency of muscle symptoms in the general population and media misinformation. When statins even at a low dosage are not tolerated other therapies can be used such as fibrate, ezetimibe nutraceuticals and antiPCSK9 antibodies. Recent data have identified other alternative therapeutic strategies such as bempedoic acid.

Summary: There are multiple strategies for the management of statin-intolerance, both pharmacological and nonpharmacological. Patient involvement in the justification of statin treatment indication and therapeutic choice is the first step to overcome misbelief and reduce nocebo effect.
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http://dx.doi.org/10.1097/MED.0000000000000595DOI Listing
April 2021

10-year comparative follow up of familial versus multifactorial chylomicronemia syndromes.

J Clin Endocrinol Metab 2020 Nov 21. Epub 2020 Nov 21.

Department of Endocrinology Louis Pradel University Hospital, Hospices Civils de Lyon, INSERM UMR 1060 Carmen, Claude Bernard Lyon 1 University, Lyon, France.

Context: The relative incidence of acute pancreatitis, ischemic cardiovascular disease and diabetes in hyperchylomicronemic patients exhibiting familial chylomicronemia syndrome (FCS), or multifactorial chylomicronemia syndrome (MCS), is unknown.

Objective: The objective was to study the occurrence of these events in FCS and MCS patients compared with the general population.

Methods: Twenty-nine FCS and 124 MCS patients, with genetic diagnosis, in four lipid clinics were matched with 413 controls. Individual hospital data linked to the national claims database were collected between 2006 and 2016. The occurrence of complications was retrospectively assessed before follow-up and during a median follow-up time of 9.8 years, for 1500 patient years of follow-up.

Results: FCS were younger than MCS (34.3 ± 13.6 vs 45.2 ± 12.6 years, p<0.01). During the study period, 58.6% of the FCS patients versus 19.4% of the MCS patients had at least one episode of acute hypertriglyceridemic pancreatitis (AHP) (HR=3.6; p<0.01). Conversely, the ischemic risk was lower in FCS than in MCS (HR=0,3; p=0.05). The risk of venous thrombosis was similar in both groups. The incidence of diabetes was high in both groups compared with matched controls (OR=22.8; p<0.01 in FCS and OR=30.3; p<0.01 in MCS).

Conclusion: The incidence of AHP was much higher in FCS than in MCS patients, whereas the incidence of ischemic cardiovascular events was found increased in MCS both versus FCS and a representative matched control group. Differences in both triglycerides-rich lipoprotein metabolism and comorbidities in MCS vs FCS drive the occurrence of different patterns of complications.
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http://dx.doi.org/10.1210/clinem/dgaa838DOI Listing
November 2020

Corrigendum to PCSK9 inhibition with alirocumab in pediatric patients with heterozygous familial hypercholesterolemia: The ODYSSEY KIDS study Volume 14, Issue 3, May-June 2020, Pages 322-330.e5.

J Clin Lipidol 2020 Sep - Oct;14(5):741

Hôpital Pitié Salpêtrière, Paris, France; Institute of Cardiometabolism and Nutrition, Paris, France.

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http://dx.doi.org/10.1016/j.jacl.2020.08.011DOI Listing
November 2020

ApoCIII: A multifaceted protein in cardiometabolic disease.

Metabolism 2020 12 12;113:154395. Epub 2020 Oct 12.

Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.

ApoCIII has a well-recognized role in triglyceride-rich lipoproteins metabolism. A considerable amount of data has clearly highlighted that high levels of ApoCIII lead to hypertriglyceridemia and, thereby, may influence the risk of cardiovascular disease. However, recent findings indicate that ApoCIII might also act beyond lipid metabolism. Indeed, ApoCIII has been implicated in other physiological processes such as glucose homeostasis, monocyte adhesion, activation of inflammatory pathways, and modulation of the coagulation cascade. As the inhibition of ApoCIII is emerging as a new promising therapeutic strategy, the complete understanding of multifaceted pathophysiological role of this apoprotein may be relevant. Therefore, the purpose of this work is to review available evidences not only related to genetics and biochemistry of ApoCIII, but also highlighting the role of this apoprotein in triglyceride and glucose metabolism, in the inflammatory process and coagulation cascade as well as in cardiovascular disease.
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http://dx.doi.org/10.1016/j.metabol.2020.154395DOI Listing
December 2020

The position of functional foods and supplements with a serum LDL-C lowering effect in the spectrum ranging from universal to care-related CVD risk management.

Atherosclerosis 2020 10 30;311:116-123. Epub 2020 Jul 30.

Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, 6200 MD, Maastricht, the Netherlands.

A wealth of data demonstrates a causal link between serum low-density lipoprotein cholesterol (LDL-C) concentrations and cardiovascular disease (CVD). Any decrease in serum LDL-C concentrations is associated with a decreased CVD risk, and this benefit is similar to a comparable LDL-C reduction after drug treatment and dietary intervention. Moreover, life-long reductions in serum LDL-C levels have a large impact on CVD risk and a long-term dietary enrichment with functional foods or supplements with a proven LDL lowering efficacy is therefore a feasible and efficient approach to decrease future CVD risk. Functional foods with an LDL-C lowering effect can improve health and/or a reduce the risk of disease. However, it has not been mentioned specifically whether this concerns mainly universal prevention or whether this can also be applied to the hierarchy towards care related prevention. Therefore, we here describe the effects of a list of interesting functional food ingredients with proven benefit in LDL-C lowering. In addition, we pay particular attention to the emerging evidence that the addition of these functional ingredients and supplements is advisable as universal and selective prevention in the general population. Moreover, functional ingredients and supplements are also helpful in care related prevention, i.e. in patients with elevated LDL-C concentrations who are statin-intolerant or are not able to achieve their LDL-C target levels. Furthermore, we will highlight practical aspects regarding the use of functional foods with an LDL-C lowering effect, such as the increasing importance of shared decision making of medical doctors and dieticians with patients to ensure proper empowerment and better adherence to dietary approaches. In addition, we will address costs issues related to the use of these functional foods, which might be a barrier in some populations.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.07.019DOI Listing
October 2020

Familial Chylomicronemia Syndrome (FCS): Recent Data on Diagnosis and Treatment.

Curr Atheroscler Rep 2020 Aug 27;22(11):63. Epub 2020 Aug 27.

Department of Endocrinology and Cardiovascular Disease Prevention, Assistance Publique-Hôpitaux de Paris, La Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.

Purpose Of Review: Familial chylomicronemia syndrome (FCS) is a rare recessive genetic disorder often underdiagnosed with potentially severe clinical consequences. In this review, we describe the clinical and biological characteristics of the disease together with its main complication, i.e., acute pancreatitis. We focused the paper on new diagnostic tools, progress in understanding the role of two key proteins (apolipoprotein CIII (apo CIII) and angiopoietin-like3 (ANGPTL-3)), and new therapeutic options.

Recent Findings: Recently, a new diagnostic tool has been proposed by European experts to help identify these patients. This tool with two recently identified parameters (low LDL and low body mass index) can help identify patients who should be genetically tested or who may have the disease when genetic testing is not available. FCS is caused by homozygous or compound heterozygous mutations of lipoprotein lipase, apolipoprotein C-II, apolipoprotein A-V, glycosylphosphatidylinositol anchored high-density lipoprotein-binding protein 1, and lipase maturation factor. Two proteins have been identified as important player in the metabolism of triglyceride-rich lipoprotein and its regulation. These two proteins are therapeutic target. Antisense oligonucleotide targeting apo CIII has been shown to significantly decrease triglyceride levels even in FCS and is the first available treatment for these patients. Further development might identify new compounds with reduced risk to develop severe thrombocytopenia. ANGPTL-3 inhibitors have not yet been tested in FCS patients but exert significant hypotriglyceridemic effect in the more frequent and less severe polygenic forms. Beyond these two new targets, microsomal triglyceride transfer protein (MTTP) inhibitors could also be part of the armamentarium, if on-going trials confirm their efficacy. New clinical tools and simple criteria can help select patients with possible FCS and identify patients who should have a genetic testing. Identifying patients with FCS is a major issue since these patients have a high risk to suffer severe episodes of acute pancreatitis and may now benefit from new therapeutic options including antisense oligonucleotide targeting apo CIII.
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http://dx.doi.org/10.1007/s11883-020-00885-1DOI Listing
August 2020

SAFEHEART risk-equation and cholesterol-year-score are powerful predictors of cardiovascular events in French patients with familial hypercholesterolemia.

Atherosclerosis 2020 08 6;306:41-49. Epub 2020 Jul 6.

Aix Marseille University, INSERM, INRA, C2VN, Marseille, France; Department of Nutrition, Metabolic Diseases, Endocrinology, La Conception Hospital, Marseille, France. Electronic address:

Background And Aims: Patients with heterozygous familial hypercholesterolemia (HeFH) present elevated cardiovascular (CV) risk. Current CV risk stratification algorithms developed for the general population are not adapted for heFH patients. It is therefore of singular importance to develop and validate CV prediction tools, which are dedicated to the HeFH population.

Methods: Our first objective was to validate the Spanish SAFEHEART-risk equation (RE) in the French HeFH cohort (REFERCHOL), and the second to compare SAFEHEART-RE with the low-density-lipoprotein-cholesterol (LDL-C)-year-score for the prediction of CV events in the HeFH French population.

Results: We included HeFH (n = 1473) patients with a genetic or clinical diagnosis (DLCN score ≥8). Among them, 512 patients with a 5-year follow-up were included to validate the 5 year-CV-RE. A total of 152 events (10.3%) occurred in the entire population of 1473 patients during a mean follow-up of 3.9 years. Over the five-year follow-up, non-fatal CV events occurred in 103 patients (20.2%). Almost all the parameters used in the SAFEHEART-RE were confirmed as strong predictors of CV events in the REFERCHOL cohort. The C-statistic revealed a satisfactory performance of both the SAFEHEART-RE and LDL-C-year-scores in predicting CV events for all the patients (primary and secondary prevention) (C-index 0.77 and 0.70, respectively) as well as for those in primary prevention at inclusion (C-index 0.78 and 0.77, respectively).

Conclusions: This analysis represents the first external validation of the SAFEHEART-RE and demonstrated that both SAFEHEART-RE and the LDL-C-year-score are good predictors of CV events in primary prevention HeFH patients.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.06.011DOI Listing
August 2020

2019 ESC/EAS Guidelines for management of dyslipidaemia: strengths and limitations.

Eur Heart J Cardiovasc Pharmacother 2020 Jul 11. Epub 2020 Jul 11.

Sorbonne Université, ACTION Study Group, INSERM UMRS_1166, Institut de cardiologie (AP-HP), Paris, France.

In 2019, the European Society of Cardiology and European Atherosclerosis Society released a new guideline document with substantial changes regarding the assessment of cardiovascular risk and treatments. The update of high-risk criteria and categories led to a better detection and primary prevention of patients at risk of a first cardiovascular event. Nonetheless, additional efforts are needed for a better inclusion of risk modifiers, especially specific to women, to improve risk stratification and direct primary prevention. Eventually, we discuss how these new guidelines implement PCSK9 inhibitors for very-high risk individuals and the evidence supporting new LDL-C goals below such as 55 mg/dL and 40 mg/dL.
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http://dx.doi.org/10.1093/ehjcvp/pvaa077DOI Listing
July 2020

Evaluation of efficacy and safety of antisense inhibition of apolipoprotein C-III with volanesorsen in patients with severe hypertriglyceridemia.

Expert Opin Pharmacother 2020 Oct 10;21(14):1675-1684. Epub 2020 Jul 10.

Department of Translational and Precision Medicine, Sapienza University of Rome , Rome, Italy.

Introduction: Severe hypertriglyceridemia (sHTG) is a complex disorder of lipid metabolism characterized by plasma levels of triglyceride (TG) greater than 885 mg/dl (>10 mmol/L). The treatment of sHTG syndromes is challenging because conventional treatments are often ineffective in reducing TG under the threshold to prevent acute pancreatitis (AP). The inhibition of , which encodes a protein involved in triglyceride (TG)-rich lipoproteins (TGRLs) removal, has been reported to be a novel target for the treatment of sHTG. Volanesorsen is a second-generation antisense oligonucleotide inhibiting apoC-III transcription/translation that has been recently approved in Europe for Familial Chylomicronemia Syndrome (FCS) treatment.

Areas Covered: This review summarizes the evidences on the efficacy and safety of volanesorsen for the treatment of sHTG syndromes.

Expert Opinion: Volanesorsen effectively reduces TG in sHTG through a mechanism that is mainly LPL-independent, potentially decreasing the risk of AP. Some safety concerns have been raised with the use of volanesorsen, mainly represented by the occurrence of thrombocytopenia. Due to the potential severity of side effects, some caution is needed before affirming the long-term utility of this drug. Despite this, volanesorsen currently remains the only drug that has been demonstrated effective in FCS, which otherwise remains an untreatable disease.
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http://dx.doi.org/10.1080/14656566.2020.1787380DOI Listing
October 2020

Carotid Atherosclerosis Evolution When Targeting a Low-Density Lipoprotein Cholesterol Concentration <70 mg/dL After an Ischemic Stroke of Atherosclerotic Origin.

Circulation 2020 Aug 29;142(8):748-757. Epub 2020 Jun 29.

Department of Neurology and Stroke Center (P.A., C.H., H.C., E.M., P.C.L., P.-J.T.).

Background: The TST trial (Treat Stroke to Target) showed the benefit of targeting a low-density lipoprotein cholesterol (LDL-C) concentration of <70 mg/dL in terms of reducing the risk of major cardiovascular events in 2860 patients with ischemic stroke with atherosclerotic stenosis of cerebral vasculature. The impact on carotid atherosclerosis evolution is not known.

Methods: TST-PLUS (Treat Stroke to Target-Plaque Ultrasound Study) included 201 patients assigned to an LDL-C concentration of <70 mg/dL and 212 patients assigned to a target of 100±10 mg/dL. To achieve these goals, investigators used the statin and dosage of their choice and added ezetimibe as needed. Ultrasonographers were certified and carotid ultrasound examinations were performed using M'Ath software at baseline and at 2, 3, and 5 years. All images were uploaded to the Intelligence in Medical Technologies database directly from the carotid ultrasound device. The central core laboratory performed all offline measurements of the intima-media thickness of both common carotid arteries blinded from the randomization arm. The main outcomes were newly diagnosed atherosclerotic plaque on carotid bifurcation or internal carotid artery using the Mannheim consensus definition and between-group comparison of common carotid arteries intima-media thickness change.

Results: After a median follow-up of 3.1 years, the achieved LDL-C concentrations were 64 mg/dL (1.64 mmol/L) in the lower-target group and 106 mg/dL (2.72 mmol/L) in the higher-target group. Compared with the higher-target group, patients in the lower-target group had a similar incidence of newly diagnosed carotid plaque: 46/201 (5-year rate, 26.1%) versus 45/212 (5-year rate, 29.7%). The change in common carotid arteries intima-media thickness was -2.69 µm (95% CI, -6.55 to 1.18) in the higher-target group and -10.53 µm (95% CI, -14.21 to -6.85) in the lower-target group, resulting in an absolute between-group difference of -7.84 µm (95% CI, -13.18 to -2.51; =0.004).

Conclusions: In patients with ischemic stroke and atherosclerosis, an LDL-C target of <70 mg/dL (1.8 mmol/L) did not reduce the incidence of new carotid plaques but produced significantly greater regression of carotid atherosclerosis than an LDL-C target of 90 to 110 mg/dL. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01252875.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046774DOI Listing
August 2020

High TG to HDL ratio plays a significant role on atherosclerosis extension in prediabetes and newly diagnosed type 2 diabetes subjects.

Diabetes Metab Res Rev 2021 Feb 20;37(2):e3367. Epub 2020 Jul 20.

Cardiovascular Prevention Unit, Department of Endocrinology and Metabolism, Paris Hospital Public Assistance, Pitié-Salpêtrière Hospital Group - Sorbonne University, Paris, France.

Aims: We investigated the role of TG to HDL ratio (TG/HDL) on atherosclerosis extension, defined as presence of coronary artery calcium (CAC), carotid and femoral plaque, in prediabetes or newly diagnosed type 2 diabetes (T2D).

Methods: We performed a retrospective, cross-sectional, single centre study involving 440 prediabetes or newly diagnosed controlled T2D subjects. Participants underwent CAC analysis by computed tomography and carotid and femoral plaque evaluation by ultrasonography and were stratified in high TG/HDL (H-TG/HDL) or low TG/HDL (L-TG/HDL) group according to TG/HDL median value. We estimated atherosclerosis extension according to the number of involved vascular districts.

Results: CAC was higher in the H-TG/HDL group than L-TG/HDL group (29.15 [0.0-95.68] vs 0.0 [0.0-53.97] AU, P < .01) and CAC > 0 was more prevalent in the H-TG/HDL group than L-TG/HDL group (64.5% vs 45%, P < .001). Femoral atherosclerosis was higher in the H-TG/HDL group than L-TG/HDL group (57.3% vs 43.6%, P < .01). H-TG/HDL group exhibited a lower prevalence of subjects with 0-TWP compared to L-TG/HDL group (21.8% vs 38.6%, P < .01) and higher percentages of subjects with 2-TWP or 3-TWP than L-TG/HDL group (for 2-TWP 29.5% vs 21.5%, P < .05; for 3-TWP 32.7% vs 20.9%, P < .01). Multiple logistic regression analysis showed that a H-TG/HDL was inversely associated to 0-TWP (P < .05) and positively associated with 2-TWP (P < .05) and 3-TWP (P < .01).

Conclusions: Our data suggest that TG/HDL is a marker of increased atherosclerotic extension in prediabetes and newly diagnosed T2D and may be useful to identify subjects with a higher cardiovascular risk profile.
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http://dx.doi.org/10.1002/dmrr.3367DOI Listing
February 2021

An innovative lipid-lowering approach to enhance attainment of low-density lipoprotein cholesterol goals.

Eur Heart J Acute Cardiovasc Care 2020 Dec 4;9(8):879-887. Epub 2020 May 4.

University Hospital Jean Minjoz, Department of Cardiology, France.

Aims: To improve attainment of LDL-cholesterol (LDL-c) targets, an expert group proposed an algorithm for lipid-lowering therapy during hospitalization for acute coronary syndrome and during follow-up. We aimed to assess adherence to this algorithm, and evaluate its impact on LDL-c levels and on attainment of therapeutic LDL-c targets in a population of post-acute coronary syndrome patients.

Methods And Results: Prospective, observational study including patients admitted for acute coronary syndrome between February 2017 and September 2018. Patients admitted without statins or ezetimibe were considered 'naïve'. Baseline LDL-c was admission LDL-c in naïve patients, and for those taking lipid-lowering therapy at admission, baseline LDL-c was back-calculated. In line with the most recent guidelines, the target was a >50% reduction in naïve LDL-c and <55 mg/dL. In total, 270 patients were analysed, mean age 67 ± 12 years, 78% men, 26% diabetic. At admission, 175 (65%) were naïve, 95 (35%) had previous lipid-lowering therapy, of which 13 (5%) statin+ezetimibe. Average LDL-c at admission was 120 ± 47 mg/dL (136 ± 44 mg/dL in naïve, 91 ± 39 mg/dL in pretreated patients). Discharge prescription was in compliance with the algorithm in 204 (76%) patients. Average LDL-c at two months was 57 ± 28 mg/dL; it was <55 mg/dL in 135 (50%), and 178 (66%) achieved a >50% reduction. Overall, 125/270 (46%) achieved the LDL-c goal. The reduction in LDL-c observed at two months persisted at five months.

Conclusion: Prescription of high-intensity statins, associated with ezetimibe where applicable, achieves LDL-c levels <55 mg/dL in 50% of patients at two months, and attains therapeutic goals defined by the European Society of Cardiology in 46% of cases.
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http://dx.doi.org/10.1177/2048872620912639DOI Listing
December 2020

PCSK9 inhibition with alirocumab in pediatric patients with heterozygous familial hypercholesterolemia: The ODYSSEY KIDS study.

J Clin Lipidol 2020 May - Jun;14(3):322-330.e5. Epub 2020 Mar 28.

Hôpital Pitié Salpêtrière, Paris, France; Institute of Cardiometabolism and Nutrition, Paris, France.

Background: Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C).

Objective: This phase 2 dose-finding study (NCT02890992) evaluated the efficacy, safety, and dose selection of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab in pediatric HeFH patients.

Methods: HeFH patients (n = 42) who were aged 8-17 years, had body weight (BW) ≥25 kg, and had LDL-C ≥130 mg/dL despite optimal statin/other lipid-modifying therapies were enrolled in 4 cohorts according to BW: cohort #1: 30 mg (<50 kg) or 50 mg (≥50 kg) every 2 weeks (Q2W), #2: 40 mg (<50 kg) or 75 mg (≥50 kg) Q2W, #3: 75 mg (<50 kg) or 150 mg (≥50 kg) every 4 weeks (Q4W), #4: 150 mg (<50 kg) or 300 mg (≥50 kg) Q4W. Primary endpoint was LDL-C % change from baseline to week 8.

Results: Mean age was 12.4 years and 95% of patients were on a statin. Baseline LDL-C levels were 160.0-188.9 mg/dL and free PCSK9 was 186.4-201.7 ng/mL across the cohorts. At week 8, the higher dose cohorts (2 and 4) demonstrated the greatest reductions in LDL-C (-46% and -45%, respectively). Free PCSK9 levels were lowest at week 8 in cohorts 2 and 4 (42.2 ng/mL and 8.6 ng/mL, respectively). Adverse events were reported in 50-90% of patients across the cohorts, and 2 patients discontinued due to adverse events.

Conclusions: In pediatric HeFH patients, LDL-C reductions were greatest in the higher dose cohorts. Alirocumab was generally well tolerated at all doses.
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http://dx.doi.org/10.1016/j.jacl.2020.03.001DOI Listing
March 2020

Proportion of High-Risk/Very High-Risk Patients in Europe with Low-Density Lipoprotein Cholesterol at Target According to European Guidelines: A Systematic Review.

Adv Ther 2020 05 21;37(5):1724-1736. Epub 2020 Mar 21.

Department of Public Health and Primary Care, Imperial Centre for Cardiovascular Disease Prevention, Imperial College London, London, UK.

Objective: Assess achievement of low-density lipoprotein cholesterol (LDL-C) targets in European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines.

Design: Systematic literature review.

Data Sources: Medline, EMBASE, Cumulated Index to Nursing and Allied Health Literature.

Eligibility Criteria: Observational studies reporting LDL-C levels/target attainment, measured between 1 August 2006 to 31 August 2017, in European adults with established cardiovascular disease (CVD), diabetes with target organ damage, familial hypercholesterolaemia (FH) or 10-year risk of fatal CVD ≥ 5% (assessed by Systematic Coronary Risk Evaluation [SCORE]).

Data Extraction And Synthesis: Two reviewers independently extracted relevant studies and assessed study quality using the Risk of Bias for Non-Randomised Studies-Interventions (ROBINS-I) tool. Primary outcome was the proportion of patients achieving LDL-C targets in the 2011/2016 ESC/EAS guidelines. Where available, patient characteristics were presented as means weighted by sample size. The proportions of patients achieving LDL-C targets in the 5 years before and after publication of the 2011 guidelines were compared using a chi-square test.

Results: Across 81 eligible studies (303,534 patients), achievement of LDL-C < 1.8 mmol/L was poor among patients with established CVD (16%; range 9-56%) and at very high risk of CVD (SCORE ≥ 10% [18%; 14-25%]). In individuals with FH, SCORE 5-10%, or diabetes and target organ damage, LDL-C < 2.5 mmol/L was achieved by 15% (9-22%), 46% (21-55%) and 13% (6-34%), respectively. Comparing the 5 years before/after publication of the 2011 guidelines, target achievement increased significantly over time but remained suboptimal (LDL-C < 1.8, 22% versus 15%; LDL-C < 2.5, 68% versus 61%; both p < 0.001; established CVD group only).

Conclusions: These data show suboptimal LDL-C control among European patients at high risk of CVD. Those at greatest overall risk (clinically established CVD or at least a 10% 10-year risk of fatal CVD) had the lowest achievement of 2011/2016 EAS/ESC LDL-C targets. With lower LDL-C targets advocated in 2019 ESC/EAS guidelines, this unmet need will increase.

Protocol Registration: PROSPERO registration number; CRD77844.
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http://dx.doi.org/10.1007/s12325-020-01285-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467492PMC
May 2020

Practice of lipoprotein apheresis and short-term efficacy in children with homozygous familial hypercholesterolemia: Data from an international registry.

Atherosclerosis 2020 04 18;299:24-31. Epub 2020 Feb 18.

Department of Paediatrics, Amsterdam University Medical Centers, Amsterdam, the Netherlands.

Background And Aims: Homozygous familial hypercholesterolemia (hoFH) may cause life-threatening atherosclerotic cardiovascular disease in childhood. Lipoprotein apheresis (LA) is considered a pivotal treatment option, but data on its efficacy, safety and optimal performance are limited. We therefore established an international registry on the execution and outcomes of LA in HoFH children. Here we report LA policies and short-term outcomes.

Methods: We approached centers worldwide, involved in LA in children with hoFH for participation. We collected information on clinical and treatment characteristics on patients aged 0-19 years between November 2016 and November 2018.

Results: We included 50 children, treated at 15 sites. Median (IQR) LDL-C levels at diagnosis, on medication and on LA were 19.2 (16.2-22.1), 14.4 (10.8-16.7) mmol/L and 4.6 mmol/L, respectively. Median (IQR) time between diagnosis and start of LA was 2.8 (1.0-4.7) years. Six (12%) patients developed cardiovascular disease during that period. Most children received LA either weekly (43%) or biweekly (37%). Seven (17%) patients reached mean LDL-C levels <3.5 mmol/L, all of them treated at least weekly. Xanthomas were present in 42 (84%) patients at diagnosis and disappeared completely in 19 (45%) on LA. Side effects of LA were minor. There were significant differences in LA conduction between sites in terms of frequency, responsible medical specialities and vascular access.

Conclusions: LA is a safe treatment and may effectively lower LDL-C in children with HoFH. However, there is room for improvement with respect to time of onset and optimization of LA therapy in terms of frequency and execution.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.01.031DOI Listing
April 2020

Efficacy and safety of alirocumab in statin-intolerant patients over 3 years: open-label treatment period of the ODYSSEY ALTERNATIVE trial.

J Clin Lipidol 2020 Jan - Feb;14(1):88-97.e2. Epub 2020 Jan 13.

Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.

Background: The 24-week randomized, double-blind ODYSSEY ALTERNATIVE trial (NCT01709513) demonstrated significant low-density lipoprotein cholesterol (LDL-C) reductions with the PCSK9 inhibitor alirocumab vs ezetimibe in statin-intolerant patients, with significantly fewer skeletal muscle events (SMEs; 32.5%) vs atorvastatin (46.0%; hazard ratio: 0.61, 95% confidence interval: 0.38 to 0.99, P = .042).

Objective: ALTERNATIVE participants could enter an open-label treatment period (OLTP) for assessment of long-term safety.

Methods: Two hundred and eighty one patients entered the OLTP; 93.7%, 84.0%, and 92.9% of patients who received atorvastatin, ezetimibe, and alirocumab, respectively, during double-blind treatment, including 216 patients (76.9%) who completed double-blind treatment, as well as patients who either prematurely discontinued treatment due to SME (n = 51 [18.1%]) or other reasons (n = 14 [5.0%]) but completed week 24 assessments. All patients in the OLTP received alirocumab (75 or 150 mg every 2 weeks based on investigator decision) for ∼3 years or until commercial availability, whichever came first.

Results: SMEs were reported by 38.4% of patients in the OLTP. Safety results from the OLTP were similar to those of the alirocumab group in the double-blind period, except for a lower rate of discontinuations due to SMEs observed with alirocumab in the OLTP (3.2% vs 15.9% in the double-blind period). At OLTP week 8, mean LDL-C reduction from baseline (=week 0 of double-blind period) was 52.0%, with reductions sustained through to the end-of-treatment visits (55.4% and 53.7% reduction at weeks 100 and 148, respectively).

Conclusions: In this population of statin-intolerant patients, alirocumab was well tolerated and produced durable LDL-C reductions over 3 years.
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http://dx.doi.org/10.1016/j.jacl.2020.01.001DOI Listing
January 2020

Statin therapy in athletes and patients performing regular intense exercise - Position paper from the International Lipid Expert Panel (ILEP).

Pharmacol Res 2020 05 19;155:104719. Epub 2020 Feb 19.

Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Lodz, Poland; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland; Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland. Electronic address:

Acute and chronic physical exercises may enhance the development of statin-related myopathy. In this context, the recent (2019) guidelines of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) for the management of dyslipidemias recommend that, although individuals with dyslipidemia should be advised to engage in regular moderate physical exercise (for at least 30 min daily), physicians should be alerted with regard to myopathy and creatine kinase (CK) elevation in statin-treated sport athletes. However it is worth emphasizing that abovementioned guidelines, previous and recent ESC/EAS consensus papers on adverse effects of statin therapy as well as other previous attempts on this issue, including the ones from the International Lipid Expert Panel (ILEP), give only general recommendations on how to manage patients requiring statin therapy on regular exercises. Therefore, these guidelines in the form of the Position Paper are the first such an attempt to summary existing, often scarce knowledge, and to present this important issue in the form of step-by-step practical recommendations. It is critically important as we might observe more and more individuals on regular exercises/athletes requiring statin therapy due to their cardiovascular risk.
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http://dx.doi.org/10.1016/j.phrs.2020.104719DOI Listing
May 2020

Benefit of Targeting a LDL (Low-Density Lipoprotein) Cholesterol <70 mg/dL During 5 Years After Ischemic Stroke.

Stroke 2020 04 20;51(4):1231-1239. Epub 2020 Feb 20.

APHP, Department of Endocrinology, Pitié-Salpêtrière hospital, Sorbonne University, Paris, France (E.B.).

Background and Purpose- The TST trial (Treat Stroke to Target) evaluated the benefit of targeting a LDL (low-density lipoprotein) cholesterol of <70 mg/dL to reduce the risk of cardiovascular events in 2860 patients with ischemic stroke with atherosclerotic stenosis of cerebral vasculature or aortic arch plaque >4 mm, in a French and Korean population. The follow-up lasted a median of 5.3 years in French patients (similar to the median follow-up time in the SPARCL trial [Stroke Prevention by Aggressive Reduction in Cholesterol Level]) and 2.0 years in Korean patients. Exposure duration to statin is a well-known driver for cardiovascular risk reduction. We report here the TST results in the French cohort. Methods- One thousand seventy-three French patients were assigned to <70 mg/dL (1.8 mmol/L) and 1075 to 100±10 mg/dL (90-110 mg/dL, 2.3-2.8 mmol/L). To achieve these goals, investigators used the statin and dosage of their choice and added ezetimibe on top if needed. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization and vascular death. Results- After a median follow-up of 5.3 years, the achieved LDL cholesterol was 66 (1.69 mmol/L) and 96 mg/dL (2.46 mmol/L) on average, respectively. The primary end point occurred in 9.6% and 12.9% of patients, respectively (HR, 0.74 [95% CI, 0.57-0.94]; =0.019). Cerebral infarction or urgent carotid revascularization following transient ischemic attack was reduced by 27% (=0.046). Cerebral infarction or intracranial hemorrhage was reduced by 28% (=0.023). The primary outcome or intracranial hemorrhage was reduced by 25% (=0.021). Intracranial hemorrhages occurred in 13 and 11 patients, respectively (HR, 1.17 [95% CI, 0.53-2.62]; =0.70). Conclusions- After an ischemic stroke of documented atherosclerotic origin, targeting a LDL cholesterol of <70 mg/dL during 5.3 years avoided 1 subsequent major vascular event in 4 (number needed to treat of 30) and no increase in intracranial hemorrhage. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01252875.
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http://dx.doi.org/10.1161/STROKEAHA.119.028718DOI Listing
April 2020

Treat stroke to target trial design: First trial comparing two LDL targets in patients with atherothrombotic strokes.

Eur Stroke J 2019 Sep 26;4(3):271-280. Epub 2019 Mar 26.

APHP, Pitié-Salpêtrière University Hospital, Pierre and Marie Curie University, Sorbonne-Paris Cité, Paris, France.

Background: In patients with non-cardio-embolic stroke, atorvastatin 80 mg/day reduced the relative risk of recurrent stroke by 16%, and a post hoc analysis showed that achieving an LDL-c of less than 70 mg/dL reduced the relative risk by 28% as compared to an on-treatment LDL of 100 mg/dL or more. Current guidelines from the French drug agency recommend treating with a statin after an ischaemic stroke to a target of less than 100 mg/dL, but no study directly tested LDL-c targets. The Treat Stroke to Target (TST) trial will compare the efficacy of achieving an LDL-c of less than 70 mg/dL versus an achieved LDL-c of 100 ± 10 mg/dL for secondary prevention in patients with recent ischaemic stroke of atherosclerotic origin.Main hypothesis: An achieved on-treatment LDL-c of less than 70 mg/dL will reduce by 25% the risk of recurrent ischaemic stroke, myocardial infarction, urgent coronary or carotid revascularisation following new symptoms requiring hospitalisation, and vascular death compared with on-treatment LDL-c of 100 ± 10 mg/dL.

Design: Patients are randomised to either LDL-c levels, and the investigator who is not blinded can use the lipid-lowering agent of his/her choice available on the market (including statins and ezetimibe), in order to achieve the assigned LDL-c level. To be eligible for enrolment, patients have a recent ischaemic stroke or TIA of atherosclerotic origin with at least one arterial stenosis of a cerebral artery, enrolled between acute phase of the qualifying stroke (once the neurological deficit is stabilised) and three months. The initial planned sample size of 3760 participants followed three years was amended to allow follow-up of all enrolled patients until 385 primary efficacy outcome events have occurred, and no later than 31 December 2019. Patients will be recruited in 76 sites in two countries (France and South Korea) between March 2010 and December 2018 (last included patient followed up to one year). Safety outcomes will include haemorrhagic strokes and new onset diabetes. All primary endpoints will be adjudicated by an endpoint committee, blinded to the assigned LDL-c level. Two sub-studies assess (1) the relative effect of assigned LDL-c levels on occurrence of new atherosclerotic plaque as detected by carotid ultrasound during follow-up, using M'ATH software for repositioning and (2) the genetic and biomarker drivers of recurrent primary endpoints according to assigned LDL-c lowering arm, in atherosclerotic strokes.

Summary: The TST trial is evaluating the benefits of achieving an LDL-c less than 70 mg/dL for secondary stroke prevention in ischaemic stroke patients of atherosclerotic origin. Main results are anticipated in 2020 or earlier (ClinicalTrials.gov NCT01252875).
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http://dx.doi.org/10.1177/2396987319838100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960693PMC
September 2019

IGF-1 is an independent predictor of retinal arterioles remodeling in subjects with uncontrolled acromegaly.

Eur J Endocrinol 2020 Mar;182(3):375-383

Department of Endocrinology, Metabolism and Cardiovascular Prevention, University Hospital Pitié-Salpêtrière, APHP, Sorbonne University Paris, Paris, France.

Context: Cardiovascular disease is one of the main causes of morbidity in active acromegaly due to the increased prevalence of risk factors and arterial consequences of increased growth hormone levels. No in vivo study has evaluated the consequences of acromegaly on the retinal microvasculature.

Objective: The aim of this study was to identify in vivo the presence of morphological alterations of retinal arterioles in subjects with acromegaly.

Patients And Methods: Single-center retrospective study of a cohort of 60 subjects with acromegaly, matched to 60 controls, who were referred for adaptive optics camera (AOC) from September 2014 to December 2016. Of the subjects with acromegaly, 19 had an active disease (AD) and 41 a controlled disease (CD) based on the IGF1 ratio (IGF1r). Retinal arteriolar remodeling was previously assessed using adaptive optics camera (AOC) in order to measure wall-to-lumen ratio (WLR), wall thickness (WT), internal diameter (ID) and wall cross sectional area (WCSA).

Results: WLR was significantly higher in AD subjects compared to CD subjects and controls (AD: 0.311 ± 0.06, CD: 0.279 ± 0.04, controls: 0.281 ± 0.04, P = 0.031). A significant positive correlation was observed between WLR and IGF-1r (R2 = 0.215, P < 0.001), even after adjustment for gender, age, systolic blood pressure (SBP) and the presence of dopamine agonist treatment (R2 = 0.406, P < 0.001). Retinal arteriolar anatomical indices were comparable between CD and controls.

Conclusion: Active acromegaly is associated with the presence of small retinal arteriolar remodeling. These results provide new perspectives to better stratify cardiovascular risk and consequently optimize treatment in acromegaly.
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http://dx.doi.org/10.1530/EJE-19-0390DOI Listing
March 2020

Efficacy and Safety of Alirocumab in Patients With Autosomal Dominant Hypercholesterolemia Associated With Proprotein Convertase Subtilisin/Kexin Type 9 Gain-of-Function or Apolipoprotein B Loss-of-Function Mutations.

Am J Cardiol 2020 03 27;125(6):880-886. Epub 2019 Dec 27.

Regeneron Pharmaceuticals, Inc., Tarrytown, New Jersey.

Autosomal dominant hypercholesterolemia results from mutations affecting the low-density lipoprotein receptor pathway, including proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GoFm) and apolipoprotein B (APOB) loss-of-function mutations (LoFm). This study examined the long-term efficacy and safety of alirocumab in patients with PCSK9 GoFm and APOB LoFm who participated in the open-label extension to a Phase 2 double-blind study (NCT01604824). Of the 23 patients who completed the 14-week double-blind period and 8-week follow-up, 21 opted to continue in the open-label extension (PCSK9 GoFm, n = 15; APOB LoFm, n = 6). Patients received alirocumab 150 mg every 2 weeks from week 32 up to 3 years for PCSK9 GoFm and 2 years for APOB LoFm. Mean duration of alirocumab exposure was 129 weeks (median: 144 weeks). After initiation of alirocumab treatment, low-density lipoprotein cholesterol (LDL-C) decreased in both groups. At week 80, mean percent reduction in LDL-C from baseline was 58.0% and 47.1% for PCSK9 GoFm and APOB LoFm groups, respectively. Treatment-emergent adverse events were reported in 19 patients (90.5%); no patients discontinued treatment due to treatment-emergent adverse events. In patients with autosomal dominant hypercholesterolemia and elevated LDL-C levels despite receiving maximally tolerated lipid-lowering therapies, alirocumab 150 mg every 2 weeks resulted in clinically meaningful reductions in LDL-C, sustained through to 3 years and 2 years for patients with PCSK9 GoFm and APOB LoFm, respectively. Alirocumab was generally well tolerated with no unexpected safety concerns.
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http://dx.doi.org/10.1016/j.amjcard.2019.12.028DOI Listing
March 2020

Quantifying atherogenic lipoproteins for lipid-lowering strategies: Consensus-based recommendations from EAS and EFLM.

Atherosclerosis 2020 02 9;294:46-61. Epub 2020 Jan 9.

Department of Clinical Chemistry, HUSLAB, Helsinki University Hospital, Helsinki, Finland.

The joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future challenges in the laboratory diagnostics of atherogenic lipoproteins. Total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and calculated non-HDL cholesterol (=total - HDL cholesterol) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. LDL cholesterol is the primary target of lipid-lowering therapies. For on-treatment follow-up, LDL cholesterol shall be measured or calculated by the same method to attenuate errors in treatment decisions due to marked between-method variations. Lipoprotein(a)-cholesterol is part of measured or calculated LDL cholesterol and should be estimated at least once in all patients at risk of ASCVD, especially in those whose LDL cholesterol decline poorly upon statin treatment. Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDL cholesterol or apolipoprotein B, especially in patients with mild-to-moderate hypertriglyceridemia (2-10 mmol/L). Non-HDL cholesterol includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. Additional apolipoprotein B measurement can detect elevated LDL particle numbers often unidentified on the basis of LDL cholesterol alone. Reference intervals of lipids, lipoproteins, and apolipoproteins are reported for European men and women aged 20-100 years. However, laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.12.005DOI Listing
February 2020

Achievement of Low-Density Lipoprotein Cholesterol Targets in CKD.

Kidney Int Rep 2019 Nov 30;4(11):1546-1554. Epub 2019 Jul 30.

Centre for Research in Epidemiology and Population Health (CESP), Inserm UMRS 1018, Villejuif, France.

Introduction: We describe the characteristics of patients with moderate/advanced chronic kidney disease (CKD) according to receipt of lipid-lowering therapy (LLT), and whether they achieved low-density lipoprotein cholesterol (LDL-C) targets for high- and very high-risk patients.

Methods: CKD-REIN (NCT03381950), a prospective cohort study conducted in 40 nephrology clinics in France, enrolled 3033 patients with moderate (stage G3) or advanced (stage G4/G5) CKD (2013-2016) who had not been on chronic dialysis or undergone kidney transplantation. Data were collected from patients' interviews and medical records. Patients were followed up at 1 year.

Results: Among 2542 patients (mean [SD] age 67 [13] years, 34% women) with LDL-C measurements at baseline (mean [SD] LDL-C 2.7 [1.1] mmol/l; cholesterol 4.8 [1.3] mmol/l), 63% were on LLT; 24% were at high (CKD stage G3, no cardiovascular disease [CVD] or diabetes) and 74% at very high (CKD stage G3 with diabetes or CVD, or CKD stage G4/5) cardiovascular risk. Among high-risk patients, 45% of those on statin and/or ezetimibe achieved the LDL-C treatment target (<2.6 mmol/l). Among very high-risk patients, the percentage at goal (<1.8 mmol/l) was 38% for CKD stage G3 and 29% for stage G4/5. There was a trend toward higher achievement of LDL-C targets with increasing LLT intensity (adjusted odds ratios for moderate vs. low intensity 1.20; 95% confidence interval 0.92-1.56; high vs. low intensity 1.46; 1.02-2.09;  = 0.036).

Conclusion: Many patients with CKD stage G3-G5 who are eligible for LLT are not treated, and those on LLT rarely achieve LDL-C targets.
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http://dx.doi.org/10.1016/j.ekir.2019.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933478PMC
November 2019

Quantifying atherogenic lipoproteins for lipid-lowering strategies: consensus-based recommendations from EAS and EFLM.

Clin Chem Lab Med 2020 03;58(4):496-517

Department of Clinical Chemistry, HUSLAB, Helsinki University Hospital, Helsinki, Finland.

The joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future challenges in the laboratory diagnostics of atherogenic lipoproteins. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLC), LDL cholesterol (LDLC), and calculated non-HDLC (=total - HDLC) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. LDLC is the primary target of lipid-lowering therapies. For on-treatment follow-up, LDLC shall be measured or calculated by the same method to attenuate errors in treatment decisions due to marked between-method variations. Lipoprotein(a) [Lp(a)]-cholesterol is part of measured or calculated LDLC and should be estimated at least once in all patients at risk of ASCVD, especially in those whose LDLC declines poorly upon statin treatment. Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDLC or apolipoprotein B (apoB), especially in patients with mild-to-moderate hypertriglyceridemia (2-10 mmol/L). Non-HDLC includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. Additional apoB measurement can detect elevated LDL particle (LDLP) numbers often unidentified on the basis of LDLC alone. Reference intervals of lipids, lipoproteins, and apolipoproteins are reported for European men and women aged 20-100 years. However, laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds.
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http://dx.doi.org/10.1515/cclm-2019-1253DOI Listing
March 2020

Free cholesterol transfer to high-density lipoprotein (HDL) upon triglyceride lipolysis underlies the U-shape relationship between HDL-cholesterol and cardiovascular disease.

Eur J Prev Cardiol 2020 Oct 15;27(15):1606-1616. Epub 2019 Dec 15.

National Institute for Health and Medical Research (INSERM) UMR_S 1166, Faculty of Medicine Pitié-Salpétrière, Paris, France.

Background: Low concentrations of high-density lipoprotein cholesterol (HDL-C) represent a well-established cardiovascular risk factor. Paradoxically, extremely high HDL-C levels are equally associated with elevated cardiovascular risk, resulting in the U-shape relationship of HDL-C with cardiovascular disease. Mechanisms underlying this association are presently unknown. We hypothesised that the capacity of high-density lipoprotein (HDL) to acquire free cholesterol upon triglyceride-rich lipoprotein (TGRL) lipolysis by lipoprotein lipase underlies the non-linear relationship between HDL-C and cardiovascular risk.

Methods: To assess our hypothesis, we developed a novel assay to evaluate the capacity of HDL to acquire free cholesterol (as fluorescent TopFluor® cholesterol) from TGRL upon in vitro lipolysis by lipoprotein lipase.

Results: When the assay was applied to several populations markedly differing in plasma HDL-C levels, transfer of free cholesterol was significantly decreased in low HDL-C patients with acute myocardial infarction (-45%) and type 2 diabetes (-25%), and in subjects with extremely high HDL-C of >2.59 mmol/L (>100 mg/dL) (-20%) versus healthy normolipidaemic controls. When these data were combined and plotted against HDL-C concentrations, an inverse U-shape relationship was observed. Consistent with these findings, animal studies revealed that the capacity of HDL to acquire cholesterol upon lipolysis was reduced in low HDL-C apolipoprotein A-I knock-out mice and was negatively correlated with aortic accumulation of [H]-cholesterol after oral gavage, attesting this functional characteristic as a negative metric of postprandial atherosclerosis.

Conclusions: Free cholesterol transfer to HDL upon TGRL lipolysis may underlie the U-shape relationship between HDL-C and cardiovascular disease, linking HDL-C to triglyceride metabolism and atherosclerosis.
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http://dx.doi.org/10.1177/2047487319894114DOI Listing
October 2020

Differentiating Familial Chylomicronemia Syndrome From Multifactorial Severe Hypertriglyceridemia by Clinical Profiles.

J Endocr Soc 2019 Dec 11;3(12):2397-2410. Epub 2019 Oct 11.

Department of Medicine, Université de Montréal and ECOGENE 21, Chicoutimi, Quebec, Canada.

Context: Differentiation between familial chylomicronemia syndrome (FCS, type 1 hyperlipoproteinemia), a rare metabolic disorder, and the more common multifactorial severe hypertriglyceridemia (sHTG, type 5 hyperlipoproteinemia) is challenging because of their overlapping symptoms but important in patient management.

Objective: To assess whether readily obtainable clinical information beyond triglycerides can effectively diagnose and differentiate patients with FCS from those with sHTG, based on well-curated data from two intervention studies of these conditions.

Methods: The analysis included 154 patients from two phase 3 clinical trials of patients with sHTG, one cohort with genetically confirmed FCS (n = 49) and one with multifactorial sHTG (n = 105). Logistic regression analyses were performed to determine the ability of variables (patient demographics, medical history, and baseline lipids, individually or in sets) to differentiate the patient populations. Receiver operating characteristics were used to determine the variable sets with the highest accuracy (percentage of times actual values matched predicted) and optimal sensitivity and specificity.

Results: The primary model diagnosed 45 of 49 patients with FCS and 99 of 105 patients with sHTG correctly. Optimal sensitivity for all available parameters (n = 17) was 91.8%, optimal specificity was 94.3%, and accuracy was 93.5%. Fasting low-density lipoprotein cholesterol (LDL-C) provided the highest individual predictability. However, a three-variable set of ultracentrifugally measured LDL-C, body mass index, and pancreatitis history differentiated the diseases with a near similar accuracy of 91.0%, and adding high-density lipoprotein cholesterol and very low-density lipoprotein cholesterol for a five-variable set provided a small incremental increase in accuracy (92.2%).

Conclusions: In the absence of genetic testing, hypertriglyceridemic patients with FCS and sHTG can be differentiated with a high degree of accuracy by analyzing readily obtainable clinical information.
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http://dx.doi.org/10.1210/js.2019-00214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864364PMC
December 2019

Pharmacokinetic and pharmacodynamic assessment of alirocumab in patients with familial hypercholesterolemia associated with proprotein convertase subtilisin/kexin type 9 gain-of-function or apolipoprotein B loss-of-function mutations.

J Clin Lipidol 2019 Nov - Dec;13(6):970-978. Epub 2019 Oct 21.

Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.

Background: Familial hypercholesterolemia is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), and causes of familial hypercholesterolemia include apolipoprotein B (APOB) loss-of-function mutations (LOFm) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm).

Objective: The aim of this study was to compare the pharmacokinetics and pharmacodynamics of alirocumab between patients with APOB LOFm vs PCSK9 GOFm.

Methods: Patients (6 APOB LOFm and 17 PCSK9 GOFm carriers) with LDL-C ≥70 mg/dL on maximally tolerated lipid-lowering therapies received alirocumab 150 mg at Weeks 0, 2, 4, and 6, placebo at Week 8, alirocumab at Week 10, placebo at Weeks 12 and 14, then completed a follow-up period at Week 22.

Results: At Week 8, mean ± standard error (SE) alirocumab concentration was lower in APOB LOFm carriers compared with PCSK9 GOFm carriers (12.12 ± 1.81 vs 16.74 ± 2.53 mg/L). APOB LOFm carriers had higher mean ± SE total PCSK9 (6.56 ± 0.73 mg/L) and lower mean ± SE free PCSK9 (0.025 ± 0.016 mg/L) at Week 8 compared with PCSK9 GOFm carriers (4.21 ± 0.35 and 0.11 ± 0.035 mg/L for total and free PCSK9, respectively). Despite this observed greater PCSK9 suppression, mean ± SE percent LDL-C reduction was lower in APOB LOFm (55.3 ± 1.0%) compared with PCSK9 GOFm carriers (73.1 ± 0.9%). Treatment-emergent adverse events occurred in 16 patients (94.1%) in the PCSK9 GOFm group and 5 patients (83.3%) in the APOB LOFm group.

Conclusions: Overall, PCSK9 inhibition with alirocumab results in clinically meaningful reductions in LDL-C in both APOB LOFm and PCSK9 GOFm carriers, although reductions were greater in the PCSK9 GOFm carriers. The results indicate a possible underlying contributor to hypercholesterolemia other than PCSK9 in patients with APOB LOFm.

Clinical Trial Registration: NCT01604824; clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.jacl.2019.10.007DOI Listing
July 2020