Benfluorex (MediatorⓇ): A look back at its side effects
Published Apr 27, 2021 • By Aurélien De Biagi
Benfluorex, sold under the trade name MediatorⓇ, was first marketed in France and European countries in 1976 by the Servier laboratories. It was withdrawn from the French market on November 30, 2009 after serious adverse effects (valvulopathy and pulmonary hypertension) were identified. Although these effects were reportedly known well before 2009, it continued to be marketed for many years.
How does MediatorⓇ work? What were the indications for this drug? Why was it withdrawn from the market? What are its side effects?
We explain it all below!
Benfluorex is the active ingredient in the drug MediatorⓇ; that is, it is the compound that provides the desired effect of the drug. It is a hypolipidemic agent (cholesterol-lowering drug) and anorectic (appetite suppressant) used to improve glycemic control and decrease insulin resistance in type 2 diabetes patients. It is a derivative of fenfluramine (indicated in the treatment of epilepsy and for its anorectic properties), which is also a member of the amphetamine class of drugs. Fenfluramine and dexfenfluramine (another derivative) were also withdrawn from the market by the FDA (Food & Drug Administration) in the US in 1997. They were reportedly the cause of valvulopathy (disease of the heart valves) and pulmonary arterial hypertension (PAH)
Benfluorex has been indicated previously as a supplement to a medically supervised diet in two cases: in case of hypertriglyceridemia and in overweight diabetes patients.
Indeed, the MediatorⓇ compound acts on the body's cells by increasing their sensitivity to insulin.
As a reminder, insulin enables the absorption of glucose (sugar) by the cells, thus decreasing glycaemia (glucose concentration in the blood).
In addition to this action, the compound is also active in the liver. It increases the synthesis of glycogen (a form of glucose storage), the increase of which leads to a decrease in appetite. It will also reduce the synthesis of triglycerides (a form of fat).
However, its anorectic properties (via its action on the liver) made it a treatment of choice for people wanting to lose weight. Although it was not originally approved by the French AMM (Autorisation de Mise sur le Marché) for weight loss, it was widely used for this purpose.
Serious adverse effects
MediatorⓇ was withdrawn from the French market in November 2009 due to its serious side effects. The AFSSAPS (the French Health Products Safety Agency), judged, after several studies, that the benefits of the drug did not outweigh the risks. This withdrawal triggered an investigation by the European Medicines Agency, ending in the European Commission's final decision to remove all drugs containing benfluorex from the EU market. As a derivative of fenfluramine, benfluorex had never been approved in the US.
Adverse effects of MediatorⓇ
Two serious adverse reactions have been identified following the use of MediatorⓇ, both of which are potentially fatal: valvulopathy mainly of the mitral and aortic valves and pulmonary arterial hypertension (PAH).
What is valvulopathy?
The cardiac valves are "flaps" in the heart that open and close according to the flow of blood (preventing it from flowing backwards). These valves are located in the heart, in between its four chambers. They therefore allow a unidirectional flow of blood and prevent mixing between oxygenated and non-oxygenated blood. There are four of these valves: the mitral valve, the aortic valve, the pulmonary valve and the tricuspid valve.
In the case of benfluorex and its derivatives, two of these will be affected: the mitral and aortic valves, located in the left heart. It is in the latter that the newly oxygenated blood from the lung flows and is propelled through the aorta to the organs and tissues of our body.
Some anorectics (particularly those of the fenfluramine family) damage these valves through the action of one of their active metabolites (a product formed during the metabolism of a molecule): norfenfluramine. Norfenfluramine activates certain cardiac receptors which leads to a chain reaction resulting in thickening and stiffness of the tricuspid valve responsible for preventing back flow (regurgitation) of blood. The consequences of valvulopathy are serious, requiring long (if not life-long) treatment, and potentially fatal. Examples include arrhythmia (heart rhythm disorders), stroke and heart failure.
What is pulmonary arterial hypertension (PAH)?
Drug-induced pulmonary arterial hypertension (PAH) is often caused by vasoconstriction of the arteries in the lungs. This narrowing of the vessels' diameter increases the pressure within the vessels. This constriction also increases vascular resistance and causes an overload on the right heart (the part of the heart that receives venous blood from the body, without oxygen, and sends it to the lungs). Eventually, this overload may lead to right heart failure. The prognosis for PAH is poor. Indeed, without treatment, life expectancy does not exceed 3 years.
Today, a number of treatments exist that can improve survival and quality of life. Medicines such as calcium channel blockers or prostacyclin aid vasodilatation. For a long time, only a lung transplant was able to help patients sustainably and effectively, but today prostacyclins are a viable alternative. However, they have their disadvantages: high cost, risk of infection (via the catheters needed for the intravenous route) and side effects (diarrhea, headaches, jaw pain).
There are also new therapies, some which are already marketed such as epoprostenol, bosentan or iloprost, some which are still under evaluation such as beraprost and treprostinil and some still in therapeutic trials for PAH, such as sildenafil.
The trial in France
The MediatorⓇ scandal involved a number of parties. The drug was developed and marketed by the French laboratory Servier.
- This Servier pharmaceutical group was and still is one of the largest French pharmaceutical companies, employing 22,000 people. With operations in many countries around the world, its research projects now focus on a wide range of therapeutic areas. Examples include: cardiovascular diseases, diabetes, neuro-psychiatric diseases and more.
- The ANSM (French National Agency for the Safety of Medicines and Health Products), formerly called the AFSSAPS (French Health Products Safety Agency), the governmental authority that guarantees the safety of medicines and health products marketed in France, was also implicated in the trial. Indeed, it is said to have failed in its mission as drug watchdog by delaying the withdrawal of benfluorex-based medications from the market.
As early as 1989, serious side effects were observed in patients taking benfluorex, notably with the withdrawal of fenfluramines from US market by the FDA in 1997. However, in France the molecule was allowed to continue to be marketed for more than ten years, after finally losing is marketing authorization at the end of 2009, thanks in particular to the intervention of a pulmonologist: Dr. Irène Frachon.
After many months (the trial opened on 23 September 2019, judgement was announced on 29 March 2021), one of the longest trials in French history has concluded. Servier Laboratories were fined €2.7 million ($3.2 million) for "aggravated deception" and "manslaughter and involuntary injury" as well as compensation to the victims or their families. The ANSM was fined €225,000 for negligent homicide and manslaughter and €78,000 for minor offences.
It is estimated that as many as 5 million people took the drug between 1976 and 2009 and that it caused heart-valve damage that killed from 500 to 2,000 French patients. While the case has now finally come to a close and the victims and their families have received some sort of justice, we can only hope that it will serve as a lesson in the importance of proper surveillance and testing of medicines before they are brought to market.
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- Benfluorex, EMA
- Dexfenfluramine side effects, Drugs.com
- Point d’information sur MédiatorⓇ (benfluorex) et ses generiques, AFSSAPS
- Hypertension artérielle pulmonaire idiopathique, Académie nationale de médecine
- Valvulopathies médicamenteuses, La lettre du cardiologue
- Médicaments de l’hypertension artérielle pulmonaire, Collège national pharmacologie médicale
- Nouveaux traitements de l’hypertension artérielle pulmonaire, Revue médicale suisse
- Affaire Mediator : l’ANSM condamnée à 303 000 euros d’amende, Infirmiers.com