7. Fenfluramine / Dexfenfluramine and Valvulopathies

Abstract

Obesity precipitates diabetes and hypertension and other known risk factors of cardiovascular diseases and stroke. Calorie control, exercise and lifestyle changes are recommended to achieve and maintain an appropriate BMI but drug therapy may also be one of the options for refractory cases. Fenfluramine marketed in 1973 and dexfenfluramine approved in 1996 were appetite-suppressant drugs widely used with phentermine (“fen-phen” or “dexfen-phen”) in the U.S.A. and other countries. They were withdrawn in September 1997 after case reports of cardiac valve abnormalities likely induced by these drugs. In many of these cases, the valvulopathies followed the long-term use, often for cosmetic purposes, even though the long-term safety was not established for these drugs. After the withdrawal, some observational studies, including an ad-hoc study of a clinical trial disrupted by safety concern, were conducted and many of them concluded that fenfluramine or dexfenfluramine increased the risk of cardiac valve abnormalities. In the study by Khan et al., the prevalence of valvulopathies was as high as 22.7% in the users of appetite suppressants compared with 1.3% in the control group, indicating that the withdrawal of fenfluramine and dexfenfluramine was the right decision. It is important to note that a serious non-rare adverse drug reaction like appetite suppressant-related valvulopathies may go unrecognized for more than 20 years. Post-marketing observational studies are valuable especially to evaluate administrative decisions, such as withdrawal, made sometimes without sufficient information.