Increased Risk of Left Heart Valve Regurgitation Associated With Benfluorex Use in Patients With Diabetes Mellitus: A Multicenter Study

Study Questions:

Is exposure to benfluorex for >3 months among patients with diabetes mellitus associated with an increased incidence of left-sided heart valve disease?

Methods:

In a reader-blinded, controlled study conducted in 10 centers in France between February 2010 and September 2011, 376 diabetic subjects previously exposed to benfluorex who were referred by a primary care physician for echocardiography and 376 diabetic control subjects were prospectively studied. Propensity scores were used to match 293 patients and 293 control subjects for age, sex, body mass index, smoking, dyslipidemia, hypertension, and coronary artery disease. The main outcome measure was the frequency of mild or greater regurgitation of a left-sided heart valve.

Results:

In the matched sample, the frequency and relative risk (odds ratio) of mild or greater left heart valve regurgitation was significantly increased among patients exposed to benfluorex compared with control subjects: 31.0% vs. 12.9% (odds ratio [OR], 3.55; 95% confidence interval [CI], 2.03-6.21) for aortic and/or mitral regurgitation, 19.8% vs. 4.7% (OR, 5.29; 95% CI, 2.46-11.4) for aortic regurgitation, and 19.4% vs. 9.6% (OR, 2.38; 95% CI, 1.27-4.45) for mitral regurgitation.

Conclusions:

The use of benfluorex was associated with a significant increase in the frequency of left heart valve regurgitation among diabetic patients. The authors suggest that the natural history of benfluorex-induced valve abnormalities requires further research.

Perspective:

Exposure to amphetamine-based appetite-suppressant drugs such as fenfluramine and dexfenfluramine has been associated with both pulmonary hypertension and left-sided heart valve regurgitation, leading to their withdrawal from the US market in 1997. Benfluorex is an amphetamine derivative related to fenfluramine and dexfenfluramine in terms of structure, clinical effect, and metabolism (hypoglycemic and hypolipidemic properties), and had been prescribed in Europe, Asia, and South Africa among patients with hypertriglyceridemia and type 2 diabetes mellitus; it also has been used off-label for weight loss. Benfluorex was withdrawn from the European market in 2010 after the publication of several reports suggesting a link between exposure to benfluorex and the occurrence of severe valve regurgitation similar to other fenfluramine derivatives. In a multicenter study in which readers were blinded to patient exposure to benfluorex, this study provides additional data supporting the occurrence of left-sided valve regurgitation among patients exposed to the drug.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Noninvasive Imaging, Prevention, Valvular Heart Disease, Atherosclerotic Disease (CAD/PAD), Echocardiography/Ultrasound, Hypertension, Mitral Regurgitation

Keywords: Outcome Assessment (Health Care), Risk, Coronary Artery Disease, South Africa, Mitral Valve Insufficiency, Hypertriglyceridemia, Europe, France, Body Mass Index, Cardiology, Heart Valve Diseases, Hypertension, Diabetes Mellitus, Echocardiography


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