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

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.

• Authors: Geneviève Derumeaux, Laura Ernande, André Serusclat, Evelyne Servan, Eric Bruckert, Hugues Rousset, Stephen Senn, Luc Van Gaal, Brigitte Picandet, François Gavini, Philippe Moulin, REGULATE trial investigators
• Journal: PloS one (PLoS One) Vol. 7 Issue 6 Pg. e38273 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22723853 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial)

Chemical References

• Glycated Hemoglobin A
• Hypoglycemic Agents
• Fenfluramine
• benfluorex

Topics

• Aged
• Diabetes Mellitus, Type 2 (complications, drug therapy)
• Echocardiography
• Female
• Fenfluramine (administration & dosage, adverse effects, analogs & derivatives, therapeutic use)
• Glycated Hemoglobin (metabolism)
• Heart Valve Diseases (diagnostic imaging, etiology)
• Humans
• Hypoglycemic Agents (administration & dosage, adverse effects, therapeutic use)
• Male
• Middle Aged
• Treatment Outcome