France: Diabetes drug may be linked to 500 deaths
(AP) â€” French health officials said Tuesday the now-banned diabetes and weight loss drug Mediator may have been linked to the deaths of about 500 people in the 33 years it was on the market.
France's health products safety agency has advised those who used the drug from 2006 to 2009 to see their doctor to check for possible heart valve problems.
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Diabetes Drug Benfluorex Linked to Thousands of Hospitalizations, Hundreds of Deaths for Valvular Disease
(Translated and adapted from theheart.org French edition)
November 19, 2010 (Saint-Denis, France) â€” The diabetes drug benfluorex (Médiator, Servier), also used off-label for the treatment of obesity in the few countries where it is approved, likely caused 500 deaths and at least 3500 hospitalizations for valvular heart disease in France since 1979, according to a second investigation by the French national health-insurance organization CNAM, which was reported at a special meeting of the drug-oversight agency AFSSAPS (French Agency for Safety of Health Products).
The meeting followed the release of a security advisory posted Tuesday by the agency that the news media there are characterizing as a new health scandal.
In late August 2010, Le Monde, reporting on the conclusions of a pharmaceutical dissertation, noted that "in recent years, Médiator may have led to between 150 and 250 hospitalizations/year and 30 deaths in France and from 500 to 1000 deaths in its 30 years of availability." The latest numbers come from a new investigation released earlier this week, initiated at the agency's request. An exact estimate of all deaths secondary to valvular disease attributable to benfluorex since it gained market approval remains difficult, since CNAM medical data are not kept longer than three years.
Nevertheless, "for a total exposure of seven million person-years between 1979 and 2009, experts estimate the number of deaths due to benfluorex at nearly 500," AFSSAPS said in its online summary.
The epidemiological analysis presented at AFSSAPS covers 48 million insured. Of these, 303 000 patients exposed to benfluorex in 2006 were identified. Monitoring was conducted for four years for hospitalizations for valvular insufficiency or multiple valvulopathy and 4.5 years for death.
"In this follow-up period, among these 303 000 patients (73% women, mean age 53 years), 597 patients were hospitalized for valvular disease, 50% had valve surgery, and 64 died, including 33 after surgery. An analysis of the most likely cause of death reveals 46 deaths attributable to valvular disease," the AFSSAPS report concludes.
Mitral- and Aortic-Valve Disease Most Prominent
In all, 556 patients were hospitalized for valvular regurgitation between 2006 and 2009, a rate of 184 per 100 000 (46 per 100 000 person-years), 303 patients (54%) were hospitalized for mitral-valve insufficiency, 270 patients (48%) for aortic regurgitation, and 77 patients (18%) for tricuspid regurgitation. Another 41 patients were hospitalized for multiple valve disorders, say the authors of the study.
In total, about 597 people who were hospitalized for valvular disease or multiple valvulopathies, 50% (298 patients) had valve replacement and 33 died postsurgery.
Pulmonary Hypertension and Death
The report also provides information on pulmonary hypertension and death, although interpretation of the data is complicated by the difficulty of distinguishing primary and secondary pulmonary hypertension in the patients' charts. Of the more than 303 000 people exposed to benfluorex in 2006, 99 were hospitalized with a diagnosis of with pulmonary hypertension or a related condition. If primary or secondary pulmonary arterial hypertension (PAH) is included in the analysis, the number of deaths believed related to benfluorex could increase.
Increasing daily doses of the drug was associated with a greater likelihood of valvular disease or death, the report notes.
Major complications also seemed to occur early. "The fact that the onset of complications may have led to patients stopping the drug makes it difficult to analyze the time to onset of complications," the authors note. "Nevertheless, an analysis of the 138 192 patients who took benfluorex in 2006 and not thereafter shows that in 62% of cases, complications arose in the same year, 21% in the following year, and 14% and 4% in years 3 and 4."
Along with the security alert, new follow-up recommendations were published by AFSSAPS on November 16.
"On the basis of available evidence, the risk of developing valvular complications that can lead to hospitalization is clear from a treatment period of three months or more," the alert reads, adding that "all the data show that the risk appears mostly in the first two years of use and persists in the two years following but declines thereafter." AFSSAPS recommends that patients who took benfluorex for at least three months during the last four years of marketing (2006–2009) consult with a physician if they have not already done so.
AFSSAPS also reminds doctors that a patient with symptoms possibly related to benfluorex should be referred to a specialist for further screening.
Discussions between AFSSAPS and CNAM are currently under way to explore the possibility of sending letters to people who took benfluorex for more than three months between November 2008 and November 2009.
A New Health Scandal for France?
Beyond the 500 deaths and hospitalizations for heart-valve disorders, experts believe lesser degrees of valvular disease could actually involve tens of thousands of patients.
Since 2000, a growing body of research has examined the cardiotoxicity of norfenfluramine, a metabolite of both dexfenfluramine (Isomeride, Servier) and benfluorex. Despite monitoring by the French national drug safety authorities since 1990, it was not until 2009 that a team led by Dr Irène Frachon (University Hospital of Brest, France) convinced French authorities to remove benfluorex from the market, well after other European countries.
Earlier this year, Servier sued Frachon and her publisher over her book about Médiator and its valvular effects, managing to have its proposed title--Médiator 150 mg: How many deaths?--successfully changed.
Franchon met with French Health Minister Xavier Bertrand yesterday--media reports suggest that one of the issues to be probed by Bertrand is whether the health authorities' inertia in withdrawing the drug was due to pressure from the company. Frachon told Ouest France that Médiator's side effects were known to officials but not promptly made public. "AFSSAPS fears the [companies], the lobbyists. That's the principal problem. We need more transparency."
Cardiologist and Member of Parliament Dr Gerard Bapt, who reportedly took up the cause after reading Frachon's book and was instrumental in having the AFSSAPS commission launch its investigation, is quoted in Le Monde asking, "How did Médiator managed to avoid the general ban on fenfluramines? The first case of valvulopathy due to Médiator in France was reported in 1999, but no action was taken. The first Spanish case of valvulopathy was reported in 2003, prompting the drug to be banned there in 2005. Two years later, Servier did not renew its application for market approval in Italy. Yet, in France, the only thing requested [of Servier] was that it conduct further studies.
Servier has responded to a number of media agencies with a statement saying that the figures being cited in the AFSSAPS report "are hypotheses founded on extrapolations."