Benfluorex, a drug related to fenfluramine, has been sold under the trade name “Mediator” by Servier Laboratories and was introduced to the French market in 1976, licenced for the treatment of type 2 diabetes and dyslipidemia. Although the evidence that benfluorex increases the risk of mild valvular regurgitant abnormalities is convincing, it is also apparent that no data exist from which to calculate the risk of death attributable to benfluorex use. Despite this, two studies have attempted to make such estimates, the results of which have been the focus of much media attention. In this review, we attempt to provide a further assessment of the evidence base, explore the limitations of the estimates of death that have been made, and calculate the population risk of mild valvular regurgitation and hospitalisation attributable to benfluorex use. We conclude that the previously published estimates of deaths attributed to the use of this agent are unsafe, based on unfounded assumptions, and are highly likely to be inaccurate.
In 2011 a media storm occurred as a result of claims that benfluorex, a Servier-manufactured drug used to treat type 2 diabetes and dyslipidemia, was responsible for “between 500 and 2000 deaths” since its introduction in 1976 [
It is helpful to briefly outline the known epidemiology and assessment of heart valve lesions to provide a context for the following discussions.
The Euro Heart Survey reported findings on 5001 men and women aged 19 to 101 years recruited across 25 European countries after assessment for valvular heart disease [
Thus valvular heart disease is common in the general population. The majority of cases are mild; indeed, in an American study [
This demonstrates an increase in prevalence by age for regurgitant lesions, the type associated with medication such as fenfluramine and benfluorex. When extrapolated to the US population, based on the census in 2000, the overall prevalence of valve disease was estimated to be 2.5% (95% CI: 2.2–2.7%). Interestingly, the overall prevalence of heart valve lesions in the Olmsted County community echocardiography cohort was lower than that in the prospective population cohort, at 1.8%, adjusted to the US population. This cohort had a much greater prevalence of white than black participants (90.3% and 2.7%, resp.), but no analysis by factors such as ethnic origin, comorbidity, or anthropometric measures was given. The disparity did appear to be greater for women, suggesting that there may be under referral compared with men. Another explanation for this disparity is that much of the valve disease in the population does not present to medical attention. As these studies did not report serial echocardiograms, it is difficult to be sure of the duration of any detected prevalent lesion, and therefore the true significance of lesions that do not present to medical attention; this disparity does suggest, however, that mild lesions may not have a significant adverse effect, a notion consistent with other data [
There are very few data describing the natural history of valve disease in populations, particularly regarding mild disease of the sort most commonly associated with medication use. Echocardiography is necessary to detect valvular heart disease reliably, but there is good evidence of marked interoperator variability in diagnosis, and, importantly, obesity reduces the ability to clearly detect mild disease. Thus knowledge of the suspected diagnosis or drug exposure may well influence interpretation of echocardiogram results, as has been demonstrated in a US study. The natural history of drug induced valvular heart disease is also unclear, with studies potentially subject to a range of confounding factors, not least the interpretation of serial echocardiographic scans. However, the available evidence relating to fenfluramine exposure suggests that resulting disease is usually mild and that it may remain stable or even improve after cessation of the causative agent.
Benfluorex, a drug related to fenfluramine, has been sold under the trade name “Mediator” by Servier Laboratories and was introduced to the French market in 1976. The initial marketing authorisation for this medication in 1974 was for the following approved indications: treatment of type II diabetic patients with body mass index greater than 25 kg/m² in combination with an appropriate diet, and secondary treatment of adult hypercholesterolaemia and hypertriglyceridaemia. In the late 1990, dexfenfluramine, a molecule related to benfluorex, was associated with regurgitant heart valve lesions in two case-control studies; in 2003 the first case report was published in which a heart valve lesion was attributed to benfluorex [
Whilst there is little disagreement about whether benfluorex, as with other related medications, might cause heart valve lesions, there is much debate as to the natural history and potential severity of these lesions, whether other factors might be important, such as genetic predisposition [
Overall, the evidence base convincingly demonstrates a causal association between benfluorex and DIVHD but does not allow calculation of the risk of hospitalisation or death attributable to benfluorex consumption. In the remaining part of this review, we will describe in detail some of the key studies which have attempted to relate benfluorex use to DIVHD, hospitalization, and death.
Two case-control studies compared benfluorex use in patients with regurgitant heart valve lesions of unknown aetiology with that in patients with defined diagnoses, for example, degenerative disease. Both studies were relatively small and could not satisfactorily account for potential confounding factors such as disease severity, comorbidities, and/or body mass index. Additionally there were methodological issues such as the use of case-control methods for a rare exposure, the lack of logistic regression analysis [
Most recently, as part of the government funded screening of individuals previously exposed to benfluorex, Tribouilloy et al. [
Weill et al. [
The Servier-sponsored REGULATE trial [
Amongst patients with repeat echocardiographic assessment (310 benfluorex and 305 pioglitazone), there were eight participants with new morphological abnormalities (valve thickening or calcification) in the benfluorex group, compared with four in the pioglitazone group (OR 1.99, 95% CI: 0.59–6.69). 27% of the benfluorex group (82 participants) and 11% of the pioglitazone group (33 participants) experienced a new valvular regurgitant lesion or worsening of an existing lesion by one or more grade (OR 2.97, 95% CI: 1.91–4.63). The vast majority of these were to grade 1 (trivial trace) with only 3 in each group progressing to grade 2 (mild); there were no cases in either group of more severe progression. The main limitation of this study is the short duration of followup, particularly considering that in the general population, benfluorex could be used for many years. The study clearly demonstrates, in this randomised, double-blind design, that benfluorex is associated with at least mild regurgitant lesions but unfortunately cannot tell us about their longer term natural history.
Despite the lack of any data on the risk of death attributable to benfluorex use in any population, two published attempts have been made to estimate the total number of deaths associated with benfluorex use from 1976 until it was removed from the market in 2009.
Hill, in 2011 [
In the first part of the paper, Professor Hill makes some interesting observations regarding the difference between “imputability”, that is, the likelihood of a particular cause of death in an individual clinical scenario, and “attributable mortality,” an epidemiological concept in which the fraction of the overall mortality attributable to use of the medication is defined at the population level. The assumptions underlying the measure of attributable risk are firstly that the risk factor (benfluorex) is causally associated with the outcome of interest and secondly that there is no confounding or bias in the measures of risk in exposed and unexposed groups. The evidence that benfluorex may cause regurgitant valvular heart lesions is substantial, and whilst the individual observational studies have significant limitations, the consistency of direction between cohort, case-control, and randomised controlled trial evidence is as conclusive as can reasonably be expected. However, this general association becomes more problematic when it is put in terms of specific numbers and used for extrapolation to the entire population. Despite the discussion of imputability and attributable risk, the author neglects the fact that no epidemiological data exist regarding the attributable risk of death due to benfluorex.
Three key issues must be examined here: firstly, the number of people at risk (clearly related to the number of boxes of medication sold) since 1976; secondly, the relative risk of hospitalisation or surgery associated with benfluorex use; and thirdly, the relative risk of death following hospitalisation or surgery associated with benfluorex use.
A major potential problem with the estimation of the number of people at risk is that there is evidence that benfluorex was used off label for weight loss, even in people who were not diabetic. However, the total number of boxes sold between 1976 and 2009 (data supplied by Servier to Afssaps), 145 million, should include all use, regardless of whether it was licensed or unlicensed.
The study uses data from the paper, by Weill et al. [
To estimate the number of hospitalizations attributable to benfluorex use the author uses the estimate of attributable risk from the cohort of diabetic benfluorex users in the earlier study by Weill et al. [
There are no epidemiological data on which to base a figure for the attributable fraction of deaths related to benfluorex use and the major assumption made by Hill [
There are several important reasons why it is unlikely that the risk of death associated with valvulopathy due to benfluorex will be the same as that due to other aetiologies. It must be acknowledged that these are hypotheses, and that there are insufficient data to confirm or refute in every case. This being the case, however, it is important that they are taken into account, when assessing the confidence with which to accept the estimates of mortality associated with benfluorex.
Firstly, even if two lesions of different origin result in similar haemodynamic consequences, the aetiological factors are likely to mean that risk of death, either due to medical complication such as heart failure or occurrence of complication following surgery, is different between causes. An example might be functional mitral regurgitation occurring as a consequence of ischaemic cardiomyopathy compared with mitral regurgitation due to benfluorex used for weight loss in an otherwise healthy patient. Clearly the associated ischaemic heart disease will substantially change the mortality risk in the first patient.
Secondly, users of benfluorex may not have the same demographic and comorbidity profile as nonusers. That is, benfluorex was prescribed for a particular indication and that indication might influence prognosis (confounding by indication). The effect of this is likely to be different according to indication, either licensed (diabetes, dyslipidemia) or unlicensed (weight loss). Thus benfluorex users are likely to be at higher risk of metabolic syndrome, hypertension, and chronic renal impairment (all associated with obesity/diabetes/dyslipidemia), all of which have implications for reduced survival than benfluorex nonusers who might present with degenerative valvulopathy. As body mass index or weight was not reported in the CNAM1 [
Thirdly, the reason for obtaining admission coding of valvular heart disease might not be similarly distributed across different aetiologies. These underlying reasons were not recorded in CNAM1 [
Fourthly, the cause of drug-induced valvular disease is liable to vary over time, that is the dose and duration of medication use will vary between individuals, and within an individual’s usage over time. Serial echocardiographic evidence pertaining to fenfluramine use suggests that nonprogression and improvement of lesion severity are possible once treatment has ceased [
Finally, the distribution of deaths between hospital and community might differ between aetiologies. This is perhaps less likely in developed countries such as France with excellent healthcare provision, but even within such populations there is evidence of differential utilisation of health services according to socioeconomic and ethnic indices [
There are further major methodological limitations. Firstly the data from the epidemiological study on which it is based [
Fournier and Zureik [
As the cohort study contains both prevalent and incident benfluorex users, the authors need to estimate the number of boxes of benfluorex used prior to 2006 and use a figure of 9 million (in contrast to the figure of 6.5 million assumed above by Hill [
The relative risk of death associated with benfluorex use is a key part of the calculations in both studies, and as in the study of Hill, the assumptions underlying the use of the data from Olmsted County by Fournier and Zureik require detailed examination.
Firstly, it is important to ask how similar are the Olmsted County population to that of the CANM1 study [
Thus the two cohorts differ markedly in terms of age range and valvular diagnosis, and given the lack of further detail could differ substantially in terms of other risk factors for mortality, namely, comorbidities, smoking and alcohol intake, body mass index, and ethnicity. It is notable in the Nkomo study that although the adjusted risk of death in Olmsted County was 1.75 (95% CI: 1.61–1.90;
It is apparent, therefore, that there are major differences between the French CNAM1 and the US Olmsted County cohorts. The differences that are conclusively demonstrated include age range and distribution of valvular diagnoses. Differences that are likely but cannot be documented because of inadequate data include body mass index, comorbidities, other medication use, smoking and alcohol consumption, and ethnicity, all of which are likely to influence mortality. Fundamentally, the key consideration is that the Nkomo paper gives mortality estimates in the general population and in a hospital-based cohort, but not in a cohort exposed to benfluorex. The use of the Nkomo estimate in the French paper can therefore really only be justified in terms of its being the only such estimate available and not in terms of its being correct. This being the case, the number of deaths estimated from the French cohort becomes difficult to support with any certainty.
Thus, in relation to attributable mortality, Fournier and Zureik make a very strong assumption. They use the RR of death of 1.75 in patients with diagnosed valvular disease relative to the general population estimated by Nkomo et al. and work out the attributable risk (RR 1.75–1/1.75) as 43% and assume that this applies to patients using benfluorex (this estimate of attributable risk of mortality is lower than the estimate of 67.7% assumed by Hill). The authors then apply this attributable risk to the number of hospitalizations and arrive at an estimate of 1320 deaths (much higher than the estimate of Hill). Within the literature there are no data on mortality attributed to benfluorex use and the authors are making a very strong assumption in applying their chosen estimate of attributable risk of mortality to hospitalized French patients. Hill took a different approach with extrapolations based on the 64 deaths occurring within the cohort of 303,000 benfluorex users. If we apply the workings out and calculations Fournier and Zureik have made to these 64 deaths, the extrapolation to the whole period between 1976 and 2009 would be 64* (78,300,000/10,317,567) *0.43, equivalent to 209 deaths, a much lower figure.
Furthermore, these estimates of attributable mortality have been presented as total figures, rather than as rates per 100,000 person-years or even as total numbers per calendar year: even if the rates were accurate, if presented in this way, they would be much less immediately alarming. The annual number of deaths attributable to benfluorex based on the papers of Hill and Zureik would then be between 15 and 39. The total annual deaths attributable to diabetes mellitus in France was 29,590 in 2001, rising to 32,156 in 2006 (5.5 and 6.1% of total population deaths, resp.) [
It is possible, however, to derive meaningful estimates of the risk of new trivial trace (grade 1) or mild (grade 2) DIVHD in diabetic patients attributable to benfluorex using published data. In the REGULATE trial, there were 82 new cases of grade 1 or 2 regurgitation at mitral, aortic, or tricuspid valves in benfluorex users. Notably, the vast majority were of progression to trivial trace (grade 1,
However, whilst these figures initially appear high, it is important to realize that the overall impact of benfluorex on disease in the population depends on how common (prevalent) its use is in diabetic patients. The cohort study by Weill et al. [
A second approach is to use the cohort study by Weill et al. [
Thus it is possible to estimate the population attributable risk associated with benfluorex use for emergence of new trivial trace/mild valvular changes and for hospitalization. There are clearly limitations with the approaches we have adopted, mainly as a result of the limitations of the underlying data, which we have elucidated earlier in this paper. Furthermore, it is clear that the existing evidence base does not permit such estimates to be made for moderate or severe valvular changes, or, crucially, for risk of death.
In conclusion, the recent estimates of mortality attributable to benfluorex use are based on unfounded assumptions and are highly likely to be inaccurate. These estimates should have been viewed with extreme caution and the necessity for further enquiry, rather than with the wholesale acceptance which has been observed in both the scientific and lay media.
Valvular heart disease is common in the general population. In an European study, of those with native heart valves, 33.9% had aortic stenosis, 24.8% mitral regurgitation, 10.4% aortic regurgitation, and 9.5% mitral stenosis. The overall prevalence of valve disease was estimated to be 2.5% in the US population. There is a convincing evidence base demonstrating a causal association between benfluorex use and mild to moderate drug induced valvular heart disease (DIVHD) in diabetic patients. There are no epidemiological studies describing the influence of benfluorex use on mortality. It is possible to derive meaningful estimates of the risk of trivial trace/mild DIVHD in diabetic patients attributable to benfluorex using published data. In patients with type 2 diabetes taking benfluorex, 59.0% of trivial trace/mild valvular regurgitation may be due to benfluorex use. The estimate of attributable risk at the population level is much lower, estimated at 5.6%, as the use of benfluorex is uncommon in diabetic patients, and the vast majority of this figure is due to trivial trace (American grade 1) changes. Despite the lack of data on the risk of death attributable to benfluorex use, two published attempts have been made to estimate the number of deaths associated with benfluorex consumption. The recent estimates of mortality attributable to benfluorex use are based on unfounded assumptions and are highly likely to be inaccurate. These estimates should have been viewed with extreme caution.
Nicholas C. Harvey has received honoraria/research funding from P and G, Alliance for Better Bone Health, Sanofi-Aventis, Schering Plough, MSD, Eli Lilly, Shire, Servier, and Amgen. Andrew Judge has received honoraria/research funding from Anthera, Servier, and Roche.
This paper summarizes the findings of an independently undertaken literature review commissioned by Servier Laboratories. The views expressed are those of the authors.