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PLoS One. 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.

Collaborators (545)

Moulin P, Bruckert E, Derumeaux G, Senn S, Van Gall L, Derumeaux G, Rousset H, Serusclat A, Ernande L, Servan E, Sinay I, Olsovsky J, Moulin P, Weisweiler P, Kumar KM, Lichiardopol R, Distiller L, Slama B, Sinay I, Faingold MC, de Lapertosa, Libman A, Maffei L, Marcucci G, Massari F, Sanchez JM, Guaymas GJ, Sosa A, Waitman J, Reissig F, Olsovsky J, Cermak O, Kvapil M, Romanova H, Cihalik C, Brezina J, Kutejova V, Hasalova Zapletalova J, Krizova J, Weisweiler P, Müller O, Mikolaiczik M, Alawi H, Wachter J, Wendisch U, Purr J, Scholz G, Hey KH, Kombächer HD, Bouzo H, Abdel Qader M, Jung T, Klausmann G, Mantz S, Speier U, Riedl M, Hennecke R, Frick HM, Urlea-Schön I, Stumpf G, Buschmann U, Kosch C, Moulin P, Emanuely P, Liotard F, Pasquini V, Pellenq B, Pellenq D, Sarradon A, Allegret JF, Caduc R, Gonzales J, Nocolas J, Pierron R, Tomas F, Touret B, Edet D, Mabire P, Morel H, Sauvage P, Alimi N, Beaudoin J, Boiche P, Chagnoux B, Charbonnier Y, Constantin G, Dedieu-Anglade N, Jacquin P, Pennetier P, Pipet L, Begey S, Curlier C, Gevrey C, Grandmottet G, Grandmottet-Egermann M, Robert G, Andre P, Adam FM, Canali T, Courtois S, Dages L, de Lemos, Dugny G, Henry JP, Herrero L, Pabst JM, Prijac B, Richard A, Rouault P, Spilthooren F, Becq JP, Bonnefoy M, Bourgeois-Adragna O, Boyes JP, Cazes C, Cerna C, Courvoisier JC, Guilloux JP, Harroch M, Mailly D, Musso S, Nabedian E, Rey F, Sastre R, Bastide V, Castelnau P, Lognos-Folco B, Martocq G, Molinier JF, Mongin G, Saraïs O, Teisseire JP, Tuszynski D, Blouin P, Cottencin JF, Delarue JM, Desvallees P, Dugue P, Durel G, Duval M, Guinet JM, Joseph C, Le Ponner C, Le Ponner-Leport C, Lemarie B, Zimmermann D, Aubert D, Biquet D, Boyer P, Campagne A, Camper E, Charbonnel L, Cochet D, Etienne JC, Giacomino A, Granier M, Humbert T, Meme B, Mercier P, Moussu P, Naud E, Oger T, Olivier Y, Pradere H, Seite P, Turot JC, Wagner-Ballon J, Delamare G, Euvrard JM, Guyon J, Kapinos R, Mestre L, Peluau J, Regnaut F, Sicard A, Sicard J, Vrinat JM, Abrial-Besson F, Blanc M, Duplan A, Fleury M, Frery-Coste M, Karsenti B, Lecaignard D, Richard J, Sarkis R, Terracol P, Thevenard E, Vincent B, Asgaraly K, Boye A, de Collart G, Eoche R, Fawaz A, Godde P, Herve B, Loquillard H, Mercier CH, Pineau-Valencienne D, Piquet P, Poivet-Ripoche L, Ridel C, Drouin M, Dubourg D, Lacroix PV, Lequeux Y, Morez Y, Mussat P, Aroun JM, Chignon JP, Couffin Y, Galvez J, Mahot D, Muller P, Steff F, Tetaud D, Thibault R, Tournemine N, Baert M, Bedouet R, Benech A, Bineau B, Blondin ML, Bonneau D, Boucher L, Bouriaud M, Buffard B, Charrier B, Daguzan B, Dasse A, Delavigne F, Desrues H, Dieumegard JY, Duroy C, Faligot S, Foubert O, Henri P, Hodebourg de Verbois F, Jean M, Larche D, Le Gall P, Marin D, Marty J, Nuel J, Osho Y, Petit A, Robert P, Savidan JY, Schaupp T, Soulard JP, Tirouflet D, Tricoire G, Baland-Peltre K, Bertrand G, Dillinger J, Frohn M, Jacques JL, Laburte P, Leyendecker P, Mauriere S, Obellianne G, Paveau A, Prochasson A, Richter D, Siegrist S, Thiebaut F, Bermond Y, Chuberre Y, Eveno MP, Le Guerroue A, Lemoine C, Marzin Y, Treguer PY, Assuncao A, Brunet E, Delbecque D, Delsart D, Grassart E, Gruchala P, Herent M, Kronek D, Lambilliotte J, Lejay D, Lopez JP, Mannessier B, Roumaneix D, Scaccia P, Vogel J, Vogel M, Weiss B, Beauchef H, Bioche P, Dahan LP, Desprez P, Gendrin V, Giroux T, Lafon P, Lejeune Wright M, Lievaux T, Limal AM, Loiselet P, Magnani C, Richir B, Rivière M, Rivoallan YM, Senk D, Vidal D, Welsing L, Colom FX, Crappier JJ, Demolliens B, Designolle P, Faugas G, Foucat J, Joly F, Jousset O, Paillard GM, Vanpraet JJ, Aim L, Audouy P, Behar M, Bekherraz A, Benady R, Bolo A, Brugnaux JP, Cohen A, de Sainte Lorette E, Delbecq D, Gleize JL, Hamou A, Huet C, Ingrand JC, Jacquety E, Jude N, Levha P, Mouchet JC, Oulmekki M, Pitoun M, Pujade HH, Sebbah A, Smila D, Tordjman J, Beignot Devalmont P, Blot E, Boulenge J, Chevallier-Salkind B, Duret Rolland M, Gontharet B, Guinot V, Marie D, Penning Reef J, Spiess HW, Yaeche P, Aupy JM, Benayoune S, Bourneuf P, Brechoire D, Dupont S, Etchegaray G, Gacioch M, Pinsembert D, Savary P, Tilly C, Churet JB, Decugis M, Flosi M, Francillotti A, Merad L, Navarre V, Pourcin J, Ripoll M, Rousseau-Durand R, Amate M, Dubois JF, Founini A, Guedon JL, Guinement E, Lanos O, Latte T, Phelippeau Y, Piffeteau-Gaston I, Rousseau G, Zalewski C, Depret Bixio G, Jambut P, Jamilloux D, Leveque Y, Migliorini P, Pradeau R, Prat J, Rouchaud E, Alaoui A, Benady M, Estadieu C, Fineltain J, Le Fevre G, Rebot J, Simmons A, Bisch O, Letzelter JM, Marmor P, Toledano J, Benhaïm R, Beugin Y, Bloud R, Bueche D, Corre B, Delachienne A, Delannay B, Duroux G, Farina M, Garrigue L, Garrigue S, Gaube JC, Giner M, Grimard E, Hocquelet JF, Jourde P, Lalanne G, Paulet C, Peraldi J, Peyre E, Pinot M, Ravaut JF, Renault E, Sampoux H, Soloy JC, Villard B, Mesnier PL, Vila M, Poupard JP, Potiez S, Masson A, Benameur D, Bernard MH, Bernhard J, Boda-Buccino M, Borys JM, Bouillot P, Boute D, Boutonnat Y, Brionnet-Metzger S, Brunel PJ, Bully C, Cambau O, Darsy P, De Botton P, Dubourg H, Halimi S, Honthaas C, Lemaire A, Navarranne A, Nicolau-Langlade S, Nocent P, Nunez S, Paffoy JC, Penet D, Pommet-Nicot C, Rochez-Fraiberg M, Roge G, Sandres-Banon D, San Galli F, Scelles V, Serusclat P, Abenhaim N, Lion A, Lousqui C, Stoll A, Ehrlich JM, Korsec P, Aerts P, Benmati Y, Cini S, Cohen S, Geromini O, Grazzini JP, Samat J, Groell R, Bindler G, Huberschwiller JL, Bismuth M, Sacareau D, Beaudoin J, Castelli B, Fhal G, Michel F, Sauli P, Parent D, Trottier G, Aicardo P, Audibert M, Auriault JR, Aussedat C, Braunsteffer T, Cohen M, Defontaine A, Garot A, Le Gall JL, Leonti F, Requin-Thimothee P, Rousseau-Durand R, Gener C, Zoro P, Ceusters T, Rost JP, Kumar K, Ganapathi B, Varthakavi P, Mutha A, Yajnik C, Rais N, Ammini AC, Mithal A, Chowdhury S, Paramesh S, Chandratreya SA, Ben Slama C, Achour A, Blouza S, Chaieb L, Djait F, Mazghani S, Jaballah I, Kacem M, Rokbani L, Salambo E, Slimane H, Zidi B, Lichiardopol R, Panus C, Paveliu F, Popescu A, Pop L, Graur M, Distiller L, van Rensburg J, Engelbrecht I, Lakha, Moore R, Vawda F, Burgess L, Blignaut S, Wellmann H, Nortje H, Kaplan H.

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.

PMID:
22723853
PMCID:
PMC3378581
DOI:
10.1371/journal.pone.0038273
[Indexed for MEDLINE]
Free PMC Article

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