A population-based study of appetite-suppressant drugs and the risk of cardiac-valve regurgitation

N Engl J Med. 1998 Sep 10;339(11):719-24. doi: 10.1056/NEJM199809103391102.


Background: Recent case reports suggest that a combination of the appetite suppressants fenfluramine and phentermine is associated with an increased risk of cardiac-valve regurgitation. There are also reports of valvular disorders in persons taking fenfluramine or dexfenfluramine alone, particularly for more than three months.

Methods: We conducted a population-based follow-up study and a nested case-control analysis of 6532 subjects who received dexfenfluramine, 2371 who received fenfluramine, and 862 who received phentermine to assess the risk of a subsequent clinical diagnosis of a valvular disorder of uncertain origin. For comparison, we identified a group of 9281 obese subjects who had not taken appetite suppressants who were matched to the treated subjects for age, sex, and weight. All subjects were free of diagnosed cardiovascular disease at the start of follow-up. The average duration of follow-up for all subjects was about four years.

Results: There were 11 cases of newly diagnosed idiopathic valvular disorders, 5 after the use of dexfenfluramine and 6 after the use of fenfluramine. There were six cases of aortic regurgitation, two cases of mitral regurgitation, and three cases of combined aortic and mitral regurgitation. There were no cases of idiopathic cardiac-valve abnormalities among the subjects who had not taken appetite suppressants or among those who took only phentermine. The five-year cumulative incidence of idiopathic cardiac-valve disorders was 0 per 10,000 subjects among those who had not taken appetite suppressants (95 percent confidence interval, 0 to 15.4) and among those who took phentermine alone (95 percent confidence interval, 0 to 76.6), 7.1 per 10,000 subjects among those who took either fenfluramine or dexfenfluramine for less than four months (95 percent confidence interval, 3.6 to 17.8; P=0.02 for the comparison with subjects who had not taken appetite suppressants), and 35.0 per 10,000 subjects among those who received either of these medications for four or more months (95 percent confidence interval, 16.4 to 76.2; P<0.001).

Conclusions: The use of fenfluramine or dexfenfluramine, particularly for four months or longer, is associated with an increased risk of newly diagnosed cardiac-valve disorders, particularly aortic regurgitation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aortic Valve Insufficiency / chemically induced*
  • Aortic Valve Insufficiency / epidemiology
  • Appetite Depressants / adverse effects*
  • Case-Control Studies
  • Drug Combinations
  • Female
  • Fenfluramine / adverse effects*
  • Follow-Up Studies
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Mitral Valve Insufficiency / chemically induced*
  • Mitral Valve Insufficiency / epidemiology
  • Obesity / complications
  • Obesity / drug therapy
  • Phentermine / adverse effects*
  • Risk
  • Survival Analysis


  • Appetite Depressants
  • Drug Combinations
  • Fenfluramine
  • Phentermine