[Targeting dyslipidaemia in primary prevention of cardiovascular disease]. / Cibler les dyslipidémies en prévention primaire des maladies cardiovasculaires.

Prevention of cardiovascular disease remains a key-objective from a health care point of view. The present article focuses on primary prevention, i.e. to prevent a first cardiovascular event among at-risk people. The first step is to evaluate the cardiovascular risk level (low to moderate, high, very high), which allows to fix target goals. It is especially the case regarding the management of dyslipidaemias. Lipid abnormalities are considered as a major coronary risk factor (especially, LDL or even better non-HDL cholesterol according to recent guidelines). Theoretically, it is quite easy to control this risk factor thanks to available lipid-lowering drugs, yet this goal remains insufficiently reached in clinical practice. The second step is to prescribe, in addition to life-style measures, the best pharmacological treatment. In most cases, it is a statin that should be well titrated, eventually combined with ezetimibe and/or bempedoic acid, to reach the set objectives. Finally, it is important to convince the at-risk individual by providing the valuable information regarding the benefits/risks ratio of the therapy and to verify a good drug compliance in the long run. Indeed, as dyslipidaemia is asymptomatic, people in primary prevention too easily tend to neglect (and eventually stop) the valuable therapy, also because statins have been widely (yet unfairly) criticized by some people in recent years.

La prévention des maladies cardiovasculaires reste un objectif prioritaire de santé publique. Cet article fait le point sur la prévention primaire, à savoir prévenir un premier événement chez des personnes considérées comme à risque. La première étape consiste à évaluer le niveau du risque (faible à modéré, élevé, très élevé), ce qui permet de fixer des objectifs thérapeutiques. C'est particulièrement le cas en ce qui concerne la prise en charge des dyslipidémies. Celles-ci sont considérées comme un facteur de risque coronarien majeur (en particulier l'augmentation du cholestérol LDL, ou encore mieux du non-HDL d'après les dernières recommandations). Ce facteur de risque est, en théorie, assez facilement modifiable avec les médicaments à notre disposition, mais reste insuffisamment contrôlé dans la pratique clinique. La seconde étape consiste à prescrire, en complément des mesures hygiéno-diététiques, le traitement pharmacologique le plus adéquat, en général une statine correctement titrée et éventuellement combinée à de l'ézétimibe et/ou à de l'acide bempédoïque, pour atteindre les objectifs fixés. Il convient, enfin, de convaincre la personne à risque en lui expliquant le rapport bénéfices/risques du traitement proposé et de s'assurer qu'une bonne observance thérapeutique soit maintenue au long cours. En effet, comme la dyslipidémie est asymptomatique, la personne en prévention primaire a trop facilement tendance à négliger, voire abandonner, ce traitement, d'autant plus que les statines ont été largement (mais injustement) décriées par certains ces dernières années.

[First-line treatment of hypercholesterolemia : start with statin monotherapy or ezetimibe-statin combination ?] / Comment je traite...une hypercholestérolémie en première intention : statine seule ou combinaison ézétimibe-statine d'emblée ?

Hypercholesterolemia, especially LDL-C («Low-Density-Lipoprotein - Cholesterol¼), is a major cardiovascular risk factor, especially for coronary artery disease. Patients at high or very high cardiovascular risk should reach LDL concentrations as low as possible («the lower, the better¼), with a reduction of at least 50 % from baseline levels according to the most recent guidelines, especially those in secondary prevention. An ezetimibe-statin combination most often allows to reach this goal thanks to a complementary action. The objectives of this article are to remind the dual actions of these two medications, to summarize the clinical evidence showing not only a remarkable cholesterol-lowering effect but also a reduction in cardiovascular events in both controlled trials and observational real-life studies, to specify the positioning of this combined oral therapy in the last international guidelines and to mention pharmaceutical specialties that combine ezetimibe with a statin available for the practitioner.

L'hypercholestérolémie, en particulier le LDL-C («Low-Density-Lipoprotein - Cholesterol¼), est un facteur de risque cardiovasculaire, notamment coronarien, majeur. Les patients à haut ou très haut risque cardiovasculaire doivent atteindre des concentrations de LDL les plus basses possibles (concept du «the lower, the better¼), avec une diminution d'au moins 50 % des valeurs de base selon les dernières recommandations, tout particulièrement ceux en prévention secondaire. Une combinaison ézétimibe-statine permet souvent d'atteindre cet objectif grâce à une action complémentaire. Le but de cet article est de rappeler la dualité des mécanismes d'action de ces deux approches, de résumer les évidences cliniques montrant non seulement un remarquable effet hypocholestérolémiant mais aussi une réduction des événements cardiovasculaires dans les essais cliniques et dans les études observationnelles de vraie vie, de préciser la position de cette combinaison thérapeutique orale dans les dernières recommandations internationales et de mentionner les spécialités pharmaceutiques associant l'ézétimibe à une statine mises à la disposition du praticien.

[Evolocumab (Repatha®) : new therapy ofhypercholesterolaemia for secondary prevention of atherosclerotic disease]. / Le médicament du mois. Évolocumab (Repatha®) : nouveau traitement de l'hypercholestérolémie pour la prévention secondaire de la maladie athéromateuse.

Evolocumab is a monoclonal antibody that blocks PCSK9 («Proproteine Convertase Subtilisine/Kexine type 9¼). It exerts a rapid, potent and sustained reduction of LDL cholesterol (LDL-c) levels in combination with statin therapy. It was first reimbursed for the treatment of familial hypercholesterolaemia. The FOURIER trial and its extension FOURIER-OLE among patients with atherosclerotic cardiovascular disease and residual hypercholesterolaemia despite statin therapy demonstrated that evolocumab significantly reduces the incidence of major cardiovascular adverse events (- 15 %, P <0.001). There was a monotonic relationship between the reduction in clinical events and the diminution of LDL-c levels even down to the lowest concentrations. The safety profile of evolocumab was excellent, also in patients with very low LDL-c levels. Because of these favorable results, evolocumab (Repatha®) is now reimbursed, under conditions, for the secondary prevention of atherosclerotic cardiovascular disease.

L'évolocumab est un anticorps monoclonal bloquant la PCSK9 («Proprotein Convertase Subtilisine/Kexine de type 9¼). Il exerce une réduction rapide, puissante et soutenue des concentrations de cholestérol LDL (LDL-c) en ajout à un traitement par statine. Il a d'abord été remboursé pour le traitement de l'hypercholestérolémie familiale. L'étude FOURIER et son extension FOURIER-OLE ont démontré, chez des patients avec ma- ladie cardiovasculaire athéromateuse et hypercholestérolémie résiduelle sous statine, que l'évolocumab est capable de réduire significativement l'incidence des événements cardiovasculaires majeurs (- 15 %, P <0,001). Il existe une relation continue entre la diminution des événements cliniques et la baisse du LDL-c, jusqu'aux valeurs les plus basses. Par contre, même aux taux les plus bas de LDL-c, la tolérance de l'évolocumab s'avère excellente. Au vu de ces résultats favorables, l'évolocumab (Repatha®) est désormais remboursé, sous conditions, pour la prévention secondaire de la maladie cardiovasculaire athéromateuse.

[Bempedoic acid and inclisiran : two new drugs to treat hypercholesterolemia]. / Acide bempédoïque et inclisiran: deux nouveaux traitements de l'hypercholestérolémie.

Last European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines on dyslipidemia published in 2019 recommend an LDL-cholesterol goal < 1.4 mmol/l (< 55 mg/dl) for people at very high cardiovascular risk. They propose combinations of lipid lowering therapies in addition to statins if necessary to meet this objective, which is very rarely reached in this at risk population. Two new drugs have recently received European Medicines Agency (EMA) approval for the treatment of hypercholesterolaemia, bempedoic acid, a small oral molecule that inhibits hepatic cholesterol synthesis, and inclisiran, a small interfering RNA that reduces PCSK9 levels after its subcutaneous injection. This article summarizes the mode of action, efficacy data, safety/tolerance profile and indications of these two innovative drugs.

Les recommandations de 2019 de l'European Society of Cardiology et de l'European Atherosclerosis Society pour le traitement des dyslipidémies préconisent un cholestérol lipoprotéine de basse densité (LDL) < 1,4 mmol/l (< 55 mg/dl) chez les sujets à très haut risque cardiovasculaire. Elles proposent des associations de médicaments hypolipémiants en addition aux statines pour rencontrer cet objectif, souvent non atteint dans cette population. Deux nouvelles médications ont reçu l'approbation de l'Agence européenne du médicament pour le traitement de l'hypercholestérolémie, l'acide bempédoïque, une médication orale qui réduit la synthèse hépatique de cholestérol, et l'inclisiran, un petit acide ribonucléique interférent qui réduit les concentrations de proprotéine convertase subtilisine/kexine de type 9. Nous résumons le mode d'action, les données d'efficacité, le profil de sécurité et les indications de ces deux classes thérapeutiques innovantes.

Evolving concepts on the management of dyslipidaemia.

It has been well established that low-density lipoproteins (LDL) and other apolipoprotein B-containing lipoproteins are causally related to atherosclerotic cardiovascular disease (ASCVD) and that lowering these lipoproteins reduces the risk of ASCVD. By lowering LDL particles as much as possible, ASCVD can be prevented. There seems to be no LDL-cholesterol (LDL-C) threshold below which no further ASCVD prevention can be achieved. Furthermore, a low (an even very low) LDL-C appears to be safe. The new ESC/EAS guidelines based on these concepts are a step towards a benefit-based strategy by focusing on the clinical benefit that can be achieved by treating the cause of ASCVD. It is recommended to lower LDL-C as much as possible to prevent ASCVD, especially in high and very high-risk patients. With these new recommendations come recognition of the importance of combination therapies in high and very high-risk patients, first with statins and ezetimibe, and if needed with a PCSK9 inhibitor. The present paper is a review of some new concepts arising during the past 10 years in the field of lipidology and the description of what is new in the 2019 EAS/ESC guidelines.

[Statins and new-onset diabetes†: benefit-risk balance]. / Effet diabétogène des statines†:balance bénéfices-risques.

Statins are the most commonly prescribed cholesterol-lowering drugs for cardiovascular prevention. Data from randomized clinical trials have shown an increased risk of diabetes mellitus type 2 (DT2) on statin treatment. These findings have been confirmed in genetic Mendelian randomization studies and in observational cohorts. The molecular mechanisms remain partly unknown. The risk of TD2 is higher with high doses of statins and in people with preexisting risk factors for T2D (prediabetes, metabolic syndrome). The cardiovascular benefit of statins overdrive by far the risk of diabetes and the prescription of statins in high risk cardiovascular subjects should not be questioned. Glycaemic monitoring and the adaptation of lifestyle and dietary measures are recommended for subjects at risk of T2D.

Les statines sont les hypocholestérolémiants les plus prescrits dans la prévention cardiovasculaire (CV). Certains essais cliniques randomisés ont révélé un risque accru de diabète de type 2 (DT2) sous statines. Ces constatations ont été confirmées par des études génétiques de randomisation mendélienne et par les données observationnelles. Les mécanismes moléculaires en cause ne sont pas clairement élucidés. Le risque de DT2 est surtout accru avec les fortes doses de statines et chez les sujets à risque de DT2 (prédiabète, syndrome métabolique). Le bénéfice CV des statines reste très supérieur au risque de diabète et la prescription de statines chez les sujets à haut risque CV ne doit pas être remise en cause. Une surveillance glycémique et l'adaptation de mesures hygiéno-diététiques sont recommandées chez les sujets à risque.

A Belgian consensus strategy to identify familial hypercholesterolaemia in the coronary care unit and its subsequent cascade screening and treatment: BEL-FaHST (The BELgium Familial Hypercholesterolaemia STrategy).

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is an autosomal dominant lipoprotein disorder characterized by significant elevation of low-density lipoprotein cholesterol (LDL-C) and markedly increased risk of premature cardiovascular disease (CVD). Because of the very high coronary artery disease risk associated with this condition, the prevalence of FH among patients admitted for CVD outmatches many times the prevalence in the general population. Awareness of this disease is crucial for recognizing FH in the aftermath of a hospitalization of a patient with CVD, and also represents a unique opportunity to identify relatives of the index patient, who are unaware they have FH. This article aims to describe a feasible strategy to facilitate the detection and management of FH among patients hospitalized for CVD. METHODS: A multidisciplinary national panel of lipidologists, cardiologists, endocrinologists and cardio-geneticists developed a three-step diagnostic algorithm, each step including three key aspects of diagnosis, treatment and family care. RESULTS: A sequence of tasks was generated, starting with the process of suspecting FH amongst affected patients admitted for CVD, treating them to LDL-C target, finally culminating in extensive cascade-screening for FH in their family. Conceptually, the pathway is broken down into 3 phases to provide the treating physicians with a time-efficient chain of priorities. CONCLUSIONS: We emphasize the need for optimal collaboration between the various actors, starting with a "vigilant doctor" who actively develops the capability or framework to recognize potential FH patients, continuing with an "FH specialist", and finally involving the patient himself as "FH ambassador" to approach his/her family and facilitate cascade screening and subsequent treatment of relatives.

[Cardiovascular protection of patients with type 2 diabetes : from EMPA-REG OUTCOME to LEADER]. / Protection cardiovasculaire du patient diabétique de type 2 : d'EMPA-REG OUTCOME à LEADER.

Two clinical trials demonstrate the superiority versus a placebo of two antidiabetic drugs in patients with type 2 diabetes and high cardiovascular risk. Empagliflozin, an inhibitor of sodium-glucose type 2 (SGLT2) cotransporters, in EMPA-REG OUTCOME, and liraglutide, an agonist of glucagon-like peptide-1 (GLP-1) receptors, in LEADER, showed a significant reduction in major cardiovascular events (- 14 and - 13 %, respectively), cardiovascular mortality (- 38 and - 22 %, respectively) and all-cause mortality (- 32 and - 15 %, respectively). A lower progression of kidney disease and less renal events were also reported. The underlying protective mechanisms remain controverted as the discussion whether the benefits are specific to each medication or could be extended to other molecules of these two pharmacological classes.

Deux essais cliniques ont démontré la supériorité versus un placebo de deux médicaments antidiabétiques chez des patients diabétiques de type 2 à haut risque cardiovasculaire. L'empagliflozine, un inhibiteur sélectif des cotransporteurs sodium-glucose de type 2 (SGLT2), dans l'étude EMPA-REG OUTCOME, et le liraglutide, un agoniste des récepteurs du glucagon-like peptide-1 (GLP-1), dans l'étude LEADER, ont montré une réduction significative des événements cardiovasculaires majeurs (respectivement, ­ 14 et ­ 13 %), de la mortalité cardiovasculaire (­ 38 et ­ 22 %) et de la mortalité globale (­ 32 et ­ 15 %). Les mécanismes sous-jacents expliquant le meilleur pronostic avec ces deux médicaments restent discutés, de même que le fait de savoir s'il s'agit d'un effet propre à chacune des molécules ou d'un effet attribuable à la classe pharmacologique.

[Therapeutic impact of screening for myocardial ischemia among asymptomatic type 2 diabetic subjects]. / Impact thérapeutique du dépistage de l'ischémie myocardique silencieuse chez le sujet diabétique de type 2.

Coronary artery disease is the major cause of mortality of type 2 diabetic subjects. Its early diagnosis to prevent progression and clinical events has intuitive appeal. Somehow, rationale for screening has not been clearly established. Screening should not modify the medical therapy because diabetic subjects have to be treated in a secondary prevention strategy. We have no data from randomized trials concerning a better outcome after revascularization in this specific population. The question how to select the high risk population to be screened has no response by now. SPECT and stress echocardiography seem valuable for screening but not for risk stratification. A large randomized clinical trial is required to confirm the cost-utility ratio of such a screening.

Familial colloid cyst of the third ventricle: neuroendocrinological follow-up and review of the literature.

Colloid cysts of the third ventricle are rare, benign cysts of endodermal origin. Between 1989 and 1999, eight patients with this lesion (five females, three males), with a mean age of 40.5 years (range 20-54), were identified out of 1354 operated for tumours of the central nervous system. Among the eight, two were familial. They were half sisters 38 and 28 years-old, who were diagnosed to have colloid cysts of the third ventricle on CT scanning. Transcortical excision yielded 10 and 15 mm sized colloid cysts, respectively. Moreover, both sisters developed a multinodular goiter associated with these congenital tumours. The second sibling developed hyperprolactinemia associated with macroprolactinemia. Pregnancy was only possible after bromocriptine treatment. These cases provide further evidences that colloid cysts probably have an autosomic recessive pattern of inheritance with variable penetrance.