Anorexigènes et maladies cardiovasculaires : les liaisons dangereuses

Les anorexigènes sont essentiellement des dérivés chimiques proches des amphétamines dont le mécanisme d’action est lié à une augmentation cérébrale de noradrénaline et/ou de sérotonine. Le développement d’une hypertension artérielle pulmonaire (HTAP) et de lésions valvulaires cardiaques, bien documentés sur plusieurs études, ont conduit à l’arrêt il y plusieurs années, des premières molécules (aminorex, fenfluramine, dexfenfluramine). Le benfluorex, introduit dans les années 1970 n’a été retiré que progressivement du marché des pays européens et très récemment en France. Si le lien entre benfluorex et HTAP ne semble pas certain, en revanche le développement de valvulopathie est bien démontré. La physiopathologie de l’HTAP et des maladies valvulaires induites par la prise d’anorexigènes n’est pas complètement élucidée. Cependant, plusieurs mécanismes ont été évoqués, dont la perte de régulation de la voie de la sérotonine ou le rôle de canaux potassium-dépendants, qui représentent les pistes les plus sérieuses.

In the past decades, obesity has been identified as an important driver of morbidity and mortality in the western countries. As a result, pharmacological approaches have been developed to fight obesity, including amphetamine-like drugs acting through a central appetite-suppressant effect. These compounds knew a significant marketing and sales success as early as the years 1960. Very soon after market access, caution has been raised on a potential risk for the cardiovascular system with the use of aminorex, leading to a first outbreak of “primary pulmonary hypertension” (PPH) in the European countries were it was available. A decade later, convincing epidemiological evidence accumulated supporting that both fenfluramine and dexfenfluramine were definite risk factor for the development of PPH, now called pulmonary arterial hypertension (PAH). In addition, these drugs appeared to be responsible for severe mitral and aortic regurgitations similar to carcinoid syndrome leading to surgery or death. Similar to aminorex, the cases of anorectic-drug induced complications abated after market withdrawal. Despite these serious warnings, the story repeated itself recently when a chemically similar compound called benfluorex, licensed to treat resistant diabetes and dyslipidemia, has been suspected to be responsible for almost identical cardiovascular complications. This is explained in a large part by the effect of norfenfluramine, the active metabolite of benfluorex, through it’s high affinity for the serotonin receptor 5-HT2B responsible for the fenfluramine-induced valvular heart diseases. Curiously, benfluorex has only been withdrawn from the French market after more than 20 years of access and six years after the first publication of suspected cases. A good decision? Very likely. The purpose of this article is to review the epidemiological and physiopathological evidence linking fenfluramine-derived drugs to cardiovascular complications, and to discuss the currently available data on benfluorex.