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AIXIAL Review #6

Cardiovascular prevention also remains topical!

 

The second cause of death in France after cancer with nearly 140,000 deaths per year and the leading cause of death in the world[1], cardiovascular diseases (CVD) remain a major public health concern that the pandemic should not make us forget. Faced with this significant burden, there are two complementary ways of proceeding: optimizing and improving the management of patients with cardiovascular diseases and ensuring that they do not occur.

The management of cardiovascular events, acute coronary syndromes or stroke, have experienced significant progress over the past twenty years as has prevention, but particularly for the latter, the figures indicate that progress remains insufficient. The adage „prevention is better than to cure“ remaining more relevant than ever, how can the situation be improved?

Medical prevention strategies take into account the overall cardiovascular risk (CVR) of having a cardiovascular accident, as a rule at 10 years. People with documented CVD are considered to be at very high risk from the outset. For others, practitioners assess risk, often using (incomplete) models such as Score[2]. But beyond these models, it is to all the factors (CVRF) and risk markers that they are attached: non-modifiable factors (age, sex, heredity), classic modifiable factors (sedentary lifestyle, smoking, obesity, hyperlipidemia, diabetes) and in addition to markers such as: chronic inflammatory diseases, Sleep Apnea Syndromes, HIV seropositivity, chronic kidney disease (see more recently for some), NASH syndrome fibrosis score (non-alcoholic fatty liver disease)[3]….

The threshold and target levels of the classic modifiable factors on which these same practitioners focus their actions are still subjects of discussion and are likely to evolve according to the results of morbid-mortality clinical trials expected by health authorities. However, lowering LDL cholesterol levels, controlling blood pressure in hypertension and HbA1c for diabetes remain constant intermediate goals.

Smoking cessation, the fight against a sedentary lifestyle, dietetic rules constitute the backbone of the preventive strategy in the general population as well as in those carrying the so-called CVRF, but in the latter, it is often necessary to resort, secondarily or sometimes even immediately (Hypertension, familial hypercholesterolemia…), to drug treatments directed specifically against one or the other of these CVRF or even more often to combine them.

The last few years have seen the development of many actions encouraging a less harmful lifestyle and many new drugs, especially for the treatment of type II diabetes[4] or hyperlipidemias to which we will pay particular attention. At the same time, NASH is the subject of intensive research and development with possible positive effects on cardiovascular risk.

Despite the optimized treatments, there remains a risk called „residual risk“ (some will see this in the interest of manufacturers, others as possible responses to a public health need). Particular attention is currently being paid to the mechanism of residual lipid risk. Beyond the responsibility of LDL cholesterol, which is not questioned, several biological abnormalities insufficiently targeted by currently available treatments help to explain it: a causal role of Lp (a) in people on statins is now well documented, hypertriglyceridemia, the role of which has been debated for a long time, the association of hypo-HDLemia with small and dense LDLs, also seem to be of particular importance in diabetic patients whose LDL levels are controlled…
Such abnormalities are potential therapeutic targets and are the subject of intensive research. Thus we see the development of both new drugs active on LDL cholesterol: inhibitors of PCSK9 (proprotein convertase subtilisin / kexin type), bempedoic acid, others preferentially directed against triglycerides: Icosapent ethyl (from fish), new fibrates, but also antisense-type therapies[5], monoclonal antibodies that inhibit ANGPTL 3[6], other antisense drugs whose main action is on Lp (a) or drugs aimed at increasing HDL (Cholesteryl ester transfer protein inhibitors).

Faced with this major issue, both commercial and public health, the aim of new targets and the arrival of new drugs deserve special attention and require careful preparation and support. For this, let us first of all keep in mind the requirements for solid clinical evidence from the health authorities, which have only grown stronger since 2005. Let us also take into account the difficulty of fixing prices for at least some of the molecules under development and let us not neglect the ambient criticism of drug misuse and unnecessary over-medicalization which encourages respect for proper use or even attempts at de-escalation of therapy[7]. Finally, let us put the issue of cardiovascular risk back into its societal and political context, which makes it above all a disease of society[8].

So how do you approach the arrival of these promising new drugs in the area of CVD prevention? Unless new more effective treatments replace the old ones, treating the residual cardiovascular risk will amount to „over-medication“. Under what conditions could this be not only acceptable but useful? These conditions are not all industrial. It is up to the latter, however, to offer a fair place for his drug, a place that can only be justified, at least initially, for high-risk patients under insufficient optimal treatment and subject to being able to have robust evidence of a clinically significant effect on cardiovascular event and death.

In order to help manufacturers find the right place for new drugs in development in cardiovascular prevention (hyperlipidemia, hypertension, diabetes, NASH syndrome, etc.) and to prepare for their arrival on the European market under the best conditions, backed by experience in terms of Health Technology Assessment and market access, in partnership with renowned experts in lipidology, taking advantage of the experience, capacity and know-how of the international CRO AIXIAL we propose to support them throughout the process of accessing the market for their medicine. To do this, we  conduct a consultation for them in order to analyze their needs, provide them with advice and training in the form of webinars and to carry out as necessary with the AIXIAL teams the clinical / epidemiological studies that will allow them to promote their medicine in the best conditions.

But beyond such a perspective, the objective of reducing the residual cardiovascular risk will only make sense if, at the same time, the use of preventive drugs improves (in which manufacturers can participate); on the other hand, if profound societal changes are underway allowing an awakening of the consciousness of our fellow citizens to their social conditioning and the possibilities of choosing lifestyles more favorable to their health (which obviously manufacturers cannot be responsible for).

— Written by Jacques Massol, MD PhD, AIXIAL consultant

[1] https://www.who.int/fr/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) et http://beh.santepubliquefrance.fr/beh/2020/24/pdf/2020_24.pdf

[2] The SCORE index (10-year cardiovascular mortality index from 40 to 65 years) is recommanded by the European Society of Cardiology

[3] Zelber-Sagi S, Schonmann Y, Yeshua H, Bentov I. Reply to: “Assessment of hepatic fibrosis in MAFLD: a new player in the evaluation of residual cardiovascular risk?”Digestive and liver disease. 2021;53(3):385–6

[4] New antidiabetics have arrived on the market such as gliflozins with some evidence of cardiovascular protection, GLP1 already well established with oral forms in development, GIP agonists (glucose-dependent insulinotropic polypeptide)

[5] Oligonucleotides used to specifically recognize a messenger RNA in order to inhibit the synthesis of the protein corresponding to this RNA

[6] ANGPTL3 or “angiopoietin like 3 is a protein involved in lipid metabolism

[7] In France, statins have been the subject of heated debate. Some of them, excessive, have discredited themselves. However, this results in a particularly French misuse of this class of drugs, resulting in over-treating primary prevention situations that do not need it and in outsourcing secondary prevention situations for which their interest is obvious; the consequences being both health and economic. Similarly, concerning the management of diabetic patients, a criticism has emerged which consists in questioning the bombarding of bi, tri or even quadruple antidiabetic therapy certain patients who could do without any drug treatment thanks to a loss. weight and physical exercise. To this should be added the old but not closed debate on the merits of the community taking charge of treatments aimed at reducing the CVR of patients who not only are not weaned from tobacco intoxication but are not even registered in a weaning trajectory…

[8] Some, in fact, following Yvan Illitch’s footsteps, will see cardiovascular disease as a reflection of a disease in our society which consumes what destroys in order to better consume what repairs then. This is why public policies, beyond pure health measures, have a place and a major responsibility in cardiovascular prevention as in those of many other pathologies favored if not created by the lifestyles that these policies impose on them

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