Anorectic drugs and cardiovascular diseases: Les Liaisons dangereuses

Abstract

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 Curiously, benfluorex has only been withdrawn from the French market after more than 20 years of access and six years after the first publication of suspected cases.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.