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Randomized Controlled Trial
. 2012;7(6):e38273.
doi: 10.1371/journal.pone.0038273. Epub 2012 Jun 19.

Echocardiographic evidence for valvular toxicity of benfluorex: a double-blind randomised trial in patients with type 2 diabetes mellitus

Geneviève Derumeaux  1 , Laura Ernande, André Serusclat, Evelyne Servan, Eric Bruckert, Hugues Rousset, Stephen Senn, Luc Van Gaal, Brigitte Picandet, François Gavini, Philippe Moulin; REGULATE trial investigators
Collaborators, Affiliations
Randomized Controlled Trial

Echocardiographic evidence for valvular toxicity of benfluorex: a double-blind randomised trial in patients with type 2 diabetes mellitus

Geneviève Derumeaux et al. PLoS One. 2012.

Abstract

Objectives: REGULATE trial was designed to compare the efficacy and safety of benfluorex versus pioglitazone in type 2 diabetes mellitus (DM) patients.

Methods: Double-blind, parallel-group, international, randomised, non-inferiority trial. More than half of the 196 participating centres were primary care centres. Patients eligible had type 2 DM uncontrolled on sulfonylurea. 846 were randomised. They received study treatment for 1 year. 423 patients were allocated to benfluorex (150 to 450 mg/day) and 423 were allocated to pioglitazone (30 to 45 mg/day). Primary efficacy criterion was HbA(1c). Safety assessment included blinded echocardiographic evaluation of cardiac and valvular status.

Results: At baseline, patients were 59.1 ± 10.5 years old with HbA1c 8.3 ± 0.8%, and DM duration 7.1 ± 6.0 years. During the study, mean HbA1c significantly decreased in both groups (benfluorex: from 8.30 ± 0.80 to 7.77 ± 1.31 versus pioglitazone: from 8.30 ± 0.80 to 7.45 ± 1.30%). The last HbA1c value was significantly lower with pioglitazone than with benfluorex (p<0.001) and non-inferiority of benfluorex was not confirmed (p = 0.19). Among the 615 patients with assessable paired echocardiography (310 benfluorex, 305 pioglitazone), 314 (51%) had at least one morphological valvular abnormality and 515 (84%) at least one functional valvular abnormality at baseline. Emergent morphological abnormalities occurred in 8 patients with benfluorex versus 4 with pioglitazone (OR 1.99), 95% CI (0.59 to 6.69). Emergent regurgitation (new or increased by one grade or more) occurred more frequently with benfluorex (82 patients, 27%) than with pioglitazone (33 patients, 11%) (OR 2.97), 95% CI (1.91 to 4.63) and were mainly rated grade 1; grade 2 (mild) was detected in 2 patients with benfluorex and 3 with pioglitazone. There was no moderate or severe regurgitation.

Conclusion: After 1 year of exposure, our results show a 2.97 fold increase in the incidence of valvular regurgitation with benfluorex and provide evidence for the valvular toxicity of this drug.

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Conflict of interest statement

Competing Interests: The authors declare the following interests: GD reports receiving honoraria for board membership from: Servier; grants supports paid to her institution from: Astra Zeneca, Actelion, Bayer; Brahms; General Electrics; Medtronic, Pfizer; Servier; Toshiba; Trophos, Travel support for scientific meetings: Actelion; Astra Zeneca, Boehringer Ingelheim, Medtronic; Pfizer, Sanofi, Servier. LE reports receiving honoraria from: Actelion, Daichi Sankyo, Servier; Travel support for scientific meetings: Pfizer, Sanofi, Servier, AS reports receiving honoraria and or travel support for scientific meetings from: Astra Zeneca, BMS, GSK, Lilly; Novartis, Pierre Fabre, Pfizzer, Sanofi, Siemens; grants supports paid to his institution from: Servier; ES reports receiving honoraria from Daichi Sankyo Servier; travel support for scientific meetings: Pfizer, Sanofi, Servier, EB reports receiving fees for presentations and participation to boards: Merck, Pfizer, Astra Zeneca, Abott, California Almond Board, Unilever, Danone, Servier, Sanofi-Avantis, MSD, Shering Plough, Genfit, AMT and NovoNordisk Hugues Rousset reports receiving grants supports paid to his institution from: Servier; SS reports receiving consulting honoraria from: Actelion; Astra-Zeneca, Auxilium; Bayer; BIOP; Biosyn; Biovitrum; Braco; Bristol-Myer Squibb; Boehringer Ingelheim; Chiesi; Chiron; Covance; CROS; Danone; Elan; Ely Lilly; Eisai; Fournier; GlaxoSmithKline; Helsinn; INOT; Jansen; Jerini; Leiras; Merck; Merz; Novartis; Novo-Nordisk; Numico; Organon; Orion; Pfizer; Pharmapart; Pharsight; Phocus; Pleiad; Pozen; Quintiles; Roche; R. W. Johnson; Sanofi; Schein; Schering; Servier; Shire; Stallergenes; Statwood; Strakan; Takeda; UCB; Unilever; Vanda; Wyeth and owning shares in Novartis and Syngenta. LVG reports receiving lecture fees from Eli Lilly and Novo Nordisk and travel reimbursement from Abbott Laboratories, AstraZeneca, Bristol-Myers-Squibb, GlaxoSmithKline, Merck, Novo Nordisk and Sanofi-Aventis and serving on advisory boards for Novo Nordisk, GlaxoSmithKline, AstraZeneca-Bristol-Myers Squibb, Eli Lilly, Merck and Servier. BP and FG report being employees of Servier. PM reports receiving payment for board membership or honoraria for presentation from: AMT, Astra Zeneca, BMS, GSK, NovoNordisk, Lilly; grants supports paid to his institution from: Astra Zeneca, Danone, MSD, Sanofi, Servier; Travel support for scientific meetings: Astra Zeneca, BMS, GSK, Merk Serono, Novartis, Lilly, MSD, Novo Nordisk, Pfizer, Sanofi, Shering Plough, Servier, Takeda. Servier previously marketed benfluorex and Takeda markets pioglitazone. There are no other patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1
Figure 1. Flow of participants.
Figure 2
Figure 2. Change in glycosylated haemoglobin (HbA1c) in the full analysis set.
Figure 3
Figure 3. Example of an emergent grade 1 aortic regurgitation in a patient treated with benfluorex.
In the parasternal views (row A) and the apical 3-chamber views (row B), grade 1 aortic regurgitation is shown by colour Doppler (arrow) after 1 year of treatment with benfluorex.
See this image and copyright information in PMC

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