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Recent case reports suggest that benfluorex, a fenfluramine derivative used in the management of overweight diabetic patients and dyslipidemia, is associated with cardiac valve regurgitation.
We conducted a case-control study. Eligible patients were those admitted in the cardiology or the cardiac surgery units of our hospital between January, 1(st)...
Context in source publication
Context 1
... patients with unexplained mitral regurgitation) and 54 gender-, admission unit-, admission date-and age-matched controls, selected among the 636 patients classified as having explained mitral regurgitation. The etiology of mitral regurgitation for the controls patients is shown in Table 1. Two controls needed to be replaced using a new selection, one because neither the patient nor the family physician could be contacted for exposure ascertainment and the other due to a language issue. ...Citations
... Ideally, future studies should have a longer follow-up period. Indeed, Benfluorex, a fenfluramine derivative designed for weight loss, was associated with mitral regurgitation after two years of use in a case-control retrospective study [71]. ...
Tirzepatide is a new molecule capable of controlling glucose blood levels by combining the dual agonism of Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide-1 (GLP-1) receptors. GIP and GLP1 are incretin hormones: they are released in the intestine in re-sponse to nutrient intake and stimulate pancreatic beta cells activity secreting insulin. GIP and GLP1 have others metabolic functions too. GLP1, in particular, reduces food intake and delays gastric emptying. Moreover, Tirzepatide has been shown to improve blood pressure and to re-duce Low-Density Lipoprotein (LDL) cholesterol and triglycerides. Tirzepatide efficacy and safety was assessed by phase III SURPASS 1-5 clinical trial program. Recently, the Food and Drug Administration approved Tirzepatide subcutaneous injection as monotherapy or combination therapy, associated with diet and physical exercise, to achieve a better glycemic blood levels in diabetic patients. Other clinical trials are currently underway to evaluate its use for in other dis-eases. The scientific interest toward this novel first-in-class medication is rapidly increasing. In this systematic review, we summarize the main results of the clinical trials investigating Tirzepatide and the currently available meta-analyses, emphasizing novel insights regarding its adoption in clinical practice for diabetes and its future potential applications in cardiovascular medicine.
... Benfluorex, also widely prescribed off-licence as a slimming-aid, has been involved in the development of fibrotic valvular diseases with restrictive motion (Carpentier type III) owing to its fenfluramine-like properties(1), resulting in its withdrawal from the market in 2009. (2)(3)(4) Caseous calcification of the mitral annulus is rarely described; it is thought to result from mitral annular calcification (MAC). This latter condition is more common in the elderly, especially in women.(5) ...
... A prospective multicenter case-control study demonstrated that the use of benfluorex was associated with a three-fold increase in the frequency of left heart valve regurgitation in diabetic patients. (12) Even though the molecule has been banned more than one decade ago from the European market following clinical observations of severe restrictive VHD following benfluorex exposure (2)(3)(4), the number of exposed patients remains considerable. ...
Background
Drug-induced valvular heart disease (DI-VHD) is a well-defined condition associated with specific pathology features. However, clinical presentations may broadly vary and thereby make DI-VHD diagnosis more challenging.
Case summary
We report two patients with a history of benfluorex administration, who developed extensive mitral calcific lesions which evolved towards caseous necrosis.
Discussion
Prospective follow-up over several years of these two patients who initially had typical DI-VHD findings provided monitoring evidence of extensive calcifications and subsequent caseous necrosis. These reports suggest a link between calcific heart injury and benfluorex exposure. The diagnosis of DI-VHD may be overlooked at this late stage.
... An association has also been identified between benfluorex exposure and development of pulmonary hypertension (Montani, Seferian, Savale, Simonneau, & Humbert, 2013). On December 2009, EMA recommended the withdrawal of benfluorex in the European Union, because its risks were deemed to be greater than its benefits (Frachon et al., 2010;Mullard, 2011;Weill et al., 2010). ...
In 2020, racemic-fenfluramine was approved in the U.S. and Europe for the treatment of seizures associated with Dravet syndrome, through a restricted/controlled access program aimed at minimizing safety risks. Fenfluramine had been used extensively in the past as an appetite suppressant, but it was withdrawn from the market in 1997 when it was found to cause cardiac valvulopathy. Available evidence indicates that appetite suppression and cardiac valvulopathy are mediated by different serotonergic mechanisms. In particular, appetite suppression can be ascribed mainly to the enantiomers d-fenfluramine and d-norfenfluramine, the primary metabolite of d-fenfluramine, whereas cardiac valvulopathy can be ascribed mainly to d-norfenfluramine. Because of early observations of markedly improved seizure control in some forms of epilepsy, fenfluramine remained available in Belgium through a Royal Decree after 1997 for use in a clinical trial in patients with Dravet syndrome at average dosages lower than those generally prescribed for appetite suppression. More recently, double-blind placebo-controlled trials established its efficacy in the treatment of convulsive seizures associated with Dravet syndrome and of drop seizures associated with Lennox-Gastaut syndrome, at doses up to 0.7 mg/kg/day (maximum 26 mg/day). Although no cardiovascular toxicity has been associated with the use of fenfluramine in epilepsy, the number of patients exposed to date has been limited and only few patients had duration of exposure longer than 3 years. This article analyzes available evidence on the mechanisms involved in fenfluramine-induced appetite suppression, antiseizure effects and cardiovascular toxicity. Despite evidence that stimulation of 5-HT2B receptors (the main mechanism leading to cardiac valvulopathy) is not required for antiseizure activity, there are many critical gaps in understanding fenfluramine's properties which are relevant to its use in epilepsy. Particular emphasis is placed on the remarkable lack of publicly accessible information about the comparative activity of the individual enantiomers of fenfluramine and norfenfluramine in experimental models of seizures and epilepsy, and on receptors systems considered to be involved in antiseizure effects. Preliminary data suggest that l-fenfluramine retains prominent antiseizure effects in a genetic zebrafish model of Dravet syndrome. If these findings are confirmed and extended to other seizure/epilepsy models, there would be an incentive for a chiral switch from racemic-fenfluramine to l-fenfluramine, which could minimize the risk of cardiovascular toxicity and reduce the incidence of adverse effects such as loss of appetite and weight loss.
... 34-36 A valvular condition-that can have weak clinical manifestations and be undiagnosed unless an echocardiogram is performed-was also hard to link with an appetite suppressant, such as the benfluorex: a casecontrol study revealed the causal association, which had been suggested by spontaneous and case-reports. 37 ...
Background
Adverse drug reactions (ADRs) are common, often preventable, and a leading cause of morbidity and mortality. Pharmacovigilance (PV) involves detection, assessment, understanding, and prevention of adverse effects or any other drug‐related problem. Education of healthcare professionals (HCPs) involved in drug prescription, dispensing and administration is essential to help prevent and mitigate both ADRs and medication errors and has to be focused on 3 pivotal aspects: • Awareness: All medicines can produce adverse effects. ADRs should always be considered as part of the differential diagnosis if any new adverse condition, symptoms or signs appear after a drug administration or during or after pharmacological treatment.
• Knowledge: HCPs must have a sound understanding of the most frequently prescribed drugs and over‐the‐counter medications, factors that make patients more likely to benefit or more susceptible to harm, as well as of causes of medication errors.
• Reporting: HCPs should know how to report ADRs and the role of reporting on regulatory aspects and scientific knowledge.
Undergraduate curricula must provide, at a minimum, sufficient skills that warrant the appropriate and safe prescription/dispensing/administration of medications in clinical practice, focusing both on therapeutic effects and prevention of harm. Clinical appraisal skills must include ADRs as differential diagnosis, taking accurate medication history, basic individual causality assessment, identification and proper management of ADRs, and informing patients of possible ADRs.
Postgraduate periodic PV training should be mandatory as part of continuing education. Specialised postgraduate education should include advanced contents.
... In the REVEAL registry conducted in US, half of enrolled patients (50.7%) presented with APAH and 46.2% were IPAH In the subgroup of APAH, CTD, CHD, portal hypertension, drugs/toxins and HIV infection corresponded to 49.9, 19.5, 10.6, 10.5, and 4.0% of the people, respectively. [6][7][8][9][10][11] age at presentation was 36 ± 15 years and the majority of the patients were females. ...
INTRODUCTION Pulmonary arterial hypertension (PAH) is defined by right-heart catheterization (RHC) showing precapillary pulmonary hypertension with a mean pulmonary artery pressure (mPAP) of >25 mmHg and a normal pulmonary artery wedge pressure (PCWP) of <15 mmHg. [1]
... Il en va de même avec le Médiator. La découverte du lien avec les valvulopathies est due au docteur Irène Frachon, qui a réalisé une enquête cas-témoins 21 . Ce n'est qu'après la décision de retrait que la CNAMTS a fait une enquête de cohorte, en comparant les patients exposés et non exposés au Médiator. ...
Baclofen safety: a strange evaluation by the French drug agency
The French drug agency decided to lower the maximum daily dose from 300 mg to 80 mg in the temporary permit for baclofen in alcohol dependence. Arguments in favor of this decision are highly questionable. They express the risks of a flawed use of big data in medicine.
... Although withdrawn from several European markets due to a suspected association with valvular heart disease, it remained available in France until 2009, when additional studies found an association with both valvular heart disease and PAH; an estimated 300,000 patients were exposed annually. [49][50][51][52][53] Figure 2 shows a timeline of anorexigen approvals. ...
Diet pills such as aminorex, fenfluramine, and dexfenfluramine have been strongly associated with the development of pulmonary arterial hypertension (PAH). Other drugs ostensibly related in function have also been implicated as “likely” associated, including amphetamine, methamphetamine, and the serotonin precursor L-tryptophan. Serotonin signaling is thought to be a mediator of diet pill–associated PAH, and it is also thought to potentially play a significant role in PAH in general. In this article, we review the evidence supporting the serotonin hypothesis in PAH in both contexts, and the potential concerns related to selective serotonin reuptake inhibitors and other medications acting on serotonin signaling pathways.
... Recent study suggests an etiological link between benfluorex and the development of PAH and mitral or aortic valvular diseases. [27] Data from the French registry showed that patients presenting benfluorex-related PAH ranged between 51 and 61 years. [6] The delay between first exposure and PAH diagnosis ranged between 5 and 12 years, suggesting that new incident cases can be expected in the next years, particularly in the elderly. ...
... Data including clinical case reports, case series, case-control studies [6], a large-scale cohort study [7] and randomized trial [8] have been accumulated leading to the consistent conclusion that benfluorex, a fenfluramine derivative, is associated with the development of cardiac valvular regurgitation. Benfluorex induces restrictive drug-induced valvular heart disease (DI-VHD). ...
There is a risk of misdiagnosis between benfluorex-induced VHD and acute rheumatic fever (ARF)-related VHD due to common characteristics of both etiologies. We aimed at estimating the probability for a patient exposed to benfluorex presenting with VHD to have, at the same time, a history of ARF-related VHD. Such epidemiological approach could help at reducing the risk of misdiagnosis. We used INSEE data and related literature as well as various modeling hypotheses to drive and test a formula for calculating the probability of a patient presenting with VHD and a history of benfluorex intake to have a prior history of ARF-related VHD. Different scenarios were estimated by a Markov model on the life course of people born in France between 1940 and 1960. Sensitivity analyses were performed under these scenarios. According to the different scenarios and gender, the probability that a patient born between 1940 and 1960 presenting with VHD and a history of benfluorex intake would have had a prior history of ARF-related VHD varied from 0.2% to 2.7%. The probabilities by the year of birth were as follows: 0.8%–2.7% for a patient born in 1940, < 0.5% in all scenarios for patients born after 1955, and < 0.2% in all scenarios for patients, born in 1960. Our results indicate that the burden of ARF-related VHD is low in the patient population exposed to benfluorex. The probability of ARF related VHD should not be over-estimated in the diagnostic procedure of VHD.
... Several studies have consistently demonstrated that fenfluramine derivatives as well as ergot alkaloids and pergolide exposure are associated with the development of restrictive heart-valve regurgitation (1)(2)(3)(4)(5). Activation of the cardiac valves 5-HT 2B receptor by norfenfluramine (active metabolite of benfluorex, dexfenfluramine and fenfluramine) ergotamine, methylergonovine (active metabolite of methysergide) and ...
Background:
We have been intrigued by the observation that aortic stenosis (AS) may be associated with characteristic features of mitral drug-induced valvular heart disease (DI-VHD) in patients exposed to valvulopathic drugs, thus suggesting that beyond restrictive heart valve regurgitation, valvulopathic drugs may be involved in the pathogenesis of AS.
Methods:
Herein are reported echocardiographic features, and pathological findings encountered in a series of patients suffering from both AS (mean gradient >15mmHg) and mitral DI-VHD after valvulopathic drugs exposure. History of rheumatic fever, chest radiation therapy, systemic disease or bicuspid aortic valve disease were exclusion criteria.
Results:
Twenty-five (19 females, mean age 62years) patients having both AS and typical features of mitral DI-VHD were identified. Mean transaortic pressure gradient was 32+/-13mmHg. Aortic regurgitation was ≥ mild in 24 (96%) but trivial in one. Known history of aortic valve regurgitation following drug initiation prior the development of AS was previously diagnosed in 17 patients (68%). Six patients underwent aortic valve replacement and 3 both aortic and mitral valve replacement. In the 9 patients with pathology analysis, aortic valvular endocardium was markedly thickened by dense non-inflammatory fibrosis, a characteristic feature of DI-VHD.
Conclusion:
The association between AS and typical mitral DI-VHD after valvulopathic drug exposure may not be fortuitous. Aortic regurgitation was usually associated to AS and preceded AS in most cases but may be lacking. Pathology demonstrated the potential role of valvulopathic drugs in the development of AS.
