Symposium| Volume 321, ISSUE 4, P285-291, April 2001

Appetite Suppressants and Valvular Heart Disease


      The association between valvular heart disease and diet pills was discovered several years ago in a small cohort of patients. Subsequent uncontrolled surveys and reports suggested a prevalence of cardiac abnormalities as high as 30%. These results led to widespread concern by millions of appetite suppressant users and the withdrawal of both fenfluramine and dexfenfluramine from the market. Through this review of the literature, it becomes apparent that we have better defined the association between valvular heart disease and appetite suppressants; nonetheless, many questions and controversies remain. Most large scale, multicenter, controlled studies have shown that a prevalence of significant valve regurgitation is between 2 and 12% and that the likelihood of disease increases with increasing dose and/or duration of appetite suppressant use, but several other issues, such as the mechanism of action, remain unanswered.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of the Medical Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Kassirer J.P.
        • Angell M.
        Prepublication release of Journal articles [editorial].
        N Engl J Med. 1997; 337: 1762-1763
        • Connolly H.M.
        • Crary J.L.
        • McGoon M.D.
        • et al.
        Valvular heart disease associated with fenfluramine-phentermine [published erratum appears in N Engl J Med 1997;337:1783].
        N Engl J Med. 1997; 337: 581-588
        • Kimmel S.E.
        • Keane M.G.
        • McCrary J.L.
        • et al.
        Detailed examination of fenfluramine-phentermine users with valve abnormalities identified in Fargo, North Dakota.
        Am J Cardiol. 1999; 84: 304-308
      1. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services interim public health recommendations, November 1997.
        MMWR Morb Mortal Wkly Rep. 1997; 46: 1061-1066
        • Singh J.P.
        • Evans J.C.
        • Levy D.
        • et al.
        Prevalence of valvular regurgitation in a population based cohort.
        Circulation. 1997; 96: I-541
        • Klein A.L.
        • Burstow D.J.
        • Tajik A.J.
        • et al.
        Age-related prevalence of valvular regurgitation in normal subjects: a comprehensive color flow examination of 118 volunteers.
        J Am Soc Echocardiogr. 1990; 3: 54-63
        • Singh J.P.
        • Evans J.C.
        • Levy D.
        • et al.
        Obesity and valvular regurgitation: is there an association [abstract]?.
        J Am Soc Echocardiogr. 1998; 11: 509
        • Kuecherer H.F.
        • Kee L.L.
        • Modin G.
        • et al.
        Echocardiography in serial evaluation of left ventricular systolic and diastolic function: importance of image acquisition, quantitation, and physiologic variability in clinical and investigational applications.
        J Am Soc Echocardiogr. 1991; 4: 203-214
        • Helmcke F.
        • Nanda N.C.
        • Hsiung M.C.
        • et al.
        Color Doppler assessment of mitral regurgitation with orthogonal planes.
        Circulation. 1987; 75: 175-183
        • Perry G.J.
        • Helmcke F.
        • Nanda N.C.
        • et al.
        Evaluation of aortic insufficiency by Doppler color flow mapping.
        J Am Coll Cardiol. 1987; 9: 952-959
        • Jick H.
        • Vasilakis C.
        • Weinrauch L.A.
        • et al.
        A population-based study of appetite-suppressant drugs and the risk of cardiac-valve regurgitation.
        N Engl J Med. 1998; 339: 719-724
        • Burger A.J.
        • Sherman H.B.
        • Charlamb M.J.
        • et al.
        Low prevalence of valvular disease in 226 phentermine-fenfluramine protocol subjects prospectively followed for up to 30 months.
        J Am Coll Cardiol. 1999; 34: 1153-1158
        • Khan M.A.
        • Herzog C.A.
        • St. Peter J.V.
        • et al.
        The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs.
        N Engl J Med. 1998; 339: 713-718
        • Weissman N.J.
        • Tighe Jr., J.F.
        • Gottdiener J.S.
        • et al.
        An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. Sustained-Release Dexfenfluramine Study Group.
        N Engl J Med. 1998; 339: 725-732
        • Wee C.
        • Phillips R.S.
        • Aurigemma G.
        • et al.
        Risk for valvular heart disease among users of fenfluramine and dexfenfluramine who underwent echocardiography before use of medication.
        . 1998; 129: 870-874
        • Jollis J.G.
        • Landolfo C.K.
        • Kisslo J.
        • et al.
        Fenfluramine and phentermine and cardiovascular findings: Effect of treatment duration on prevalence of valve abnormalities.
        Circulation. 2000; 101: 2071-2077
        • Gardin J.A.
        • Schumacher
        • Constantine G.
        • et al.
        Valvular abnormalities and cardiovascular status following exposure to dexfenfluramine or phentermine/fenfluramine.
        JAMA. 2000; 283: 1703-1709
        • Shively B.K.
        • Roldan C.A.
        • Gill E.A.
        • et al.
        Prevalence and determinants of valvulopathy in patients treated with dexfenfluramine.
        Circulation. 2000; 100: 2161-2167
        • Gross S.B.
        • Lepor N.E.
        • Daley W.L.
        • et al.
        Dose and duration of appetite suppressant therapy impacts incidence of valvular heart disease.
        Circulation. 1998; 98: I-28
        • Mitchell P.
        • Smythe G.
        Hormonal responses to fenfluramine in depressed and control subjects.
        J Affect Disord. 1990; 60: 321-343
        • Maher T.J.
        • Ulus J.H.
        • Wurtman R.J.
        Phentermine and other monoamine-oxidase inhibitors may increase plasma serotonin when given with fenfluramines.
        Lancet. 1999; 353: 38
        • Balcioglu A.
        • Wurtman R.J.
        Effects of fenfluramine and phentermine (fen-phen) on dopamine and serotonin release in rat striatum: in vivo microdialysis study in conscious animals.
        Brain Res. 1998; 813: 67-72
        • Weissman N.J.
        • Panza J.A.
        • Tighe J.F.
        • et al.
        Natural history of valvular regurgitation one year after discontinuation of dexfenfluramine.
        Ann Intern Med. 2001; 134: 267-273
        • Bonow R.O.
        • Carabello B.
        • de Leon Jr., A.C.
        • et al.
        Guidelines for the management of patients with valvular heart disease: executive summary: A report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on Management of Patients with Valvular Heart Disease).
        Circulation. 1998; 98: 1949-1984