Appetite-suppressant drugs and the risk of primary pulmonary hypertension

Authors: Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, et al (for the International Primary Pulmonary Hypertension Study Group).
Source: New England Journal of Medicine. 335:609-16. August 29, 1996.
Institutions: McGill University and multiple institutions in the United States and Europe.
Financial support: Medical Research Council of Canada, Institut de Recherches Internationales Servier and Ministry of Public Health and Environment of Belgium.



Appetite suppressing agents including phentermine, fenfluramine and dexfenfluramine are increasingly being used for the treatment of obesity. Phentermine is chemically related to the amphetamines and shares their potential for drug dependence and exacerbation of cardiovascular problems. Fenfluramine and dexfenfluramine are not amphetamine-like, but have been associated with rare cases of unexplained ("primary") pulmonary hypertension, some fatal. This case-control study was designed to look at risk factors for the development of primary pulmonary hypertension, in particular in relation to the use of anorexic drugs.


Results Authors' Discussion

In their discussion, the authors review a number of potential sources of bias and confounding.

The authors conclude that their results are unlikely to be the result of chance or bias, and that the increased risk of pulmonary hypertension with use of anorexic agents for periods longer than one year might even be higher; not enough data are available yet to answer this question. Also, there is not enough data to speculate on whether these results apply only to the derivates of fenfluramine or to other appetite suppressing drugs as well.


An editorial (complete text from NEJM) by Drs. JoAnn Manson and Gerald Faich argues that the risk of primary pulmonary hypertension must be balanced against the health risks of obesity. They go on to estimate the risk-benefit ratio in the following fashion:


The study presented here seems well designed and documents a significant increase in a small baseline risk of "primary" pulmonary hypertension, caused by the use of appetite suppressant drugs. What the risk will be when these agents are used for periods longer than a year remains to be seen. Also, too few patients used only the amphetamine-like preparations to make any statements about them. To my knowledge, they have not yet been linked to pulmonary hypertension. Undetected selection bias is always a risk with case-control studies. The actual risk associated with the use of these agents could, thus, be somewhat higher or lower.

The editorial has generated controversy, reported in the media, because its authors have had financial ties to the pharmaceutical industry producing these drugs. This issue aside, I believe that the analysis presented in the editorial, which yielded a benefit:risk ratio of 20:1 is problematic, for a number of reasons.

Thus, although there may well be an overall benefit to the use of anorexic agents, especially in patients with risk factors for obesity-related diseases, the risk:benefit estimate provided in the editorial seems optimistically biased.

Randomized trials looking at these drugs vs. placebo, and at different drugs taken for different periods of time are needed soon, since the public demand for these medications is likely to increase rapidly. In the absence of randomized trials, close surveillance of patients receiving these agents for prolonged periods of time will be essential. Perhaps a national registry should be considered.


Reader comments

September 15, 1996

The Lancet has an editorial that relates to this study.

October 3, 1996

 The New England Journal of Medicine has published an editorial piece about the conflict of interest issue related to the editorial about this study. The authors of that editorial respond in a letter to the editor.

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