Diet Drugs and Death

It has been known for quite awhile that drug-induced valvulopathy is an issue for fenfluramines (diet drugs).

Fenfluramine, which was sold as Pondimin, Ponderax and Adifax, was one part of a two drug combination sold as Fen-Phen for anti-obesity.  Fenfluramine was removed from the U.S. market in 1997 following reports of heart valve disease and pulmonary hypertension.    The other medication in the diet combination was phentermine.

Fenfluramine is a mixture of dextrofenfluramine and levofenfluramine (i.e. it's racemic mixture of two enantiomoers).  It causes an increase in the neurotransmitor serotonin.  Serotonin is known to be responsible for mood and appetite.  The increase in serotonin leads to the sensation of feeling full and not hungry.  It is postulated that fenfluramine, a sympathomimetic amine, causes release of serotonin and inhibits the reuptake of serotonin.  High levels of serotonin are found to decrease appetite in humans.

Fenfluramine, however, has "off-target" effects via activation of 5-hydroxytryptamine (5-HT) 2B receptor (5-HT2BR) expressed on heart valve leaflets.  This leads to a growth on the heart valves, leaving them structurally changed and incapable of closing properly.  Clinically, this can be detected by cardiovascular symptoms, which include a heart murmur, shortness of breath (dyspnea), edema, chest pain, congestive heart failure (CHF), palpitations, as well as supraventricular tachycardia. These symptoms are well described in the New England Journal of Medicine.

Macroscopic appearance: anterior leaflet 
of the mitral valve
 with thickened and retractile insertion 
of the chordae tendineae.

It is postulated that fenfluramine, a sympathomimetic amine, causes release of serotonin and inhibits the reuptake of serotonin.  As noted above, high levels of serotonin are found to decrease appetite in humans.  Elevated serotonin is also associated with acute or chronic pulmonary hypertension from pulmonary vasoconstriction or cardiac valve fibrosis (endocardial fibrosis) from overstimulation of serotonic growth receptors on fibrocytes.  Additionally increased serotonin levels are a factor in retroperitoneal fibrosis.

Serotonin is an intense pulmonary vasoconstrictor that stimulates proleferation of vascular smooth muscle by interacting synergistically with platelet-derived growth factor.

Why Did France Wait To Pull A Weight Loss Drug?

It took years for France to pull Mediator (benfluorex) from its market.  But why did it take so long for the French Regulatory Authority, Afssaps, to force Servier to remove it from the Market in 2009?  The drug was being used for weight loss.  It was developed by the French pharma company, Servier, and approved by Regulators 35 years ago.  The drug, however was said to have been the cause of death for 2000 people.

In 1999 there was an official report that Mediator could cause heart disease, yet it stayed on the French market  for an additional 10 years.  What could be the reason?

In 2000, according to Martine Verdier, an attorney representing victims, "there was a scientific study that demonstrated the side effects."  Valvular heart disease was the issue.  This is not the first time that there was an association between a medication being used for weight loss and valvular heart disease and associated pulmonary hypertension.  In fact, according to The New York Times there were two other Servier wight-loss medications, which were closely related to Mediator that were at the center of the infamous fen-phen scandal in the late 1990s in the United States.

Mediator (benfluorex) is an amphetamine derivative.  Fenfluramine and dexfenfluramine  are amphetamine derivatives and were licensed to companies in the US and then marketed by Wyeth as the drug combination for wight loss.  In September 1997 the FDA announced the withdrawal of fenfluramine and dexfenfluramine.  Dexfenfluramine was manufactured for Interneuron Pharmaceuticals and marketed under the name of Redux by Wyeth, which also manufactured  and marketed fenfluramine under the brand name Pondimin. Both companies  agreed to voluntarily withdraw their drugs.  Nevertheless, Mediator remained available to the French public.


Servier stands accused of misleading the public over the ingredients of the Mediator.  The French government has accused the company of consumer fraud and manslaughter.  After Servier was granted a market approval for Mediator as a diabetes drug, it promoted the drug as a prescription for weight loss.  This was done to increase the sales of the drug, unfortunately it also increased the number of patients harmed.

Following this scandal, the head of the French equivalent to the FDA known as Afssaps resigned.  France has since implemented reforms to Afssaps, which is now known as Ansm.  The new French National Agency of Medicine and Health Products Safety is hoped to revamp the French Regulatory Agency and establish new trust and confidence following the scandal over Mediator.