Silver Lining to the Cloud over Anorexogen-Related Cardiac Valvulopathy?

• Appetite depressants
• Mitral valve insufficiency
• Aortic valve insufficiency
• Fenfluramine
• Dexfenfluramine

Pharmacologic appetite suppression has been used as an alternative strategy in the treatment of obesity for four decades. Anorexogen therapy is a more “attractive” method of losing weight than prolonged, often unsuccessful dietary restriction or gastric bypass or stapling procedures that facilitate gastric emptying. The appetite-suppressing effect of anorexogens is mediated by altering serotonin kinetics; phentermine inhibits clearance of serotonin in the lungs, and fenfluramine stimulates its release and blocks its neuronal reuptake. The common aim of the different therapies, used singly or in combination, is to reduce the morbidity due to coronary heart disease, stroke, and hypertension associated with obesity.

Initially, fenfluramine (introduced in 1959) and phentermine (introduced in 1973) were used individually for short-term therapy (<3 months). These agents were well tolerated and resulted in reduction in body weight without serious complications, except for rare reports of pulmonary hypertension (1). In 1992, a series of long-term studies of weight control (2) suggested that long-term combination therapy with fenfluramine and phentermine (“fen-phen”) was more effective in treatment of obesity. Subsequently, the number of prescriptions for dexfenfluramine (the dextro isomer of fenfluramine) and fenfluramine–phentermine skyrocketed. By late 1995, approximately 15 million prescriptions had been filled, predominantly for young to middle-aged women. Unfortunately, societal condemnation of obesity fueled the explosion in use of anorexogen treatment, which extended to casual use for cosmetic weight loss, particularly in minimally overweight, nonobese women.

Treatment of obesity with fenfluramine–phentermine was abruptly halted in 1997, when both agents were voluntarily withdrawn from the market by the manufacturer. This withdrawal was prompted by a public health advisory from the U.S. Food and Drug Administration (3) in response to the report of 24 patients treated with …