Anti-Obesity Drugs in Trouble as Research Continues

Anti-Obesity Drugs in Trouble as Research Continues

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Sep-Oct 98	Rank Last Period Jul-Aug 98
1	F.M. Sacks, et al., "The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels," New Engl. J. Med., 335(14):1001-9, 3 October 1996. [8 U.S. and Canadian institutions] *VL459 49 2	49	2
2	S.M. Hammer, et al., "A controlled trial with two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less," New Engl. J. Med., 337(11):725-33, 11 September 1997. [15 U.S. and U.K. institutions] *XV174	31	1
3	E. Gluckman, et al., "Outcome of cord-blood transplantation from related and unrelated donors," New Engl. J. Med., 337(6):373-81, 7 August 1997. [9 institutions worldwide] *XP407	27	†
4	J.A. Staessen, et al., "Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension," The Lancet, 350(9080):757-64, 13 September 1997. [14 institutions worldwide] *XW282	24	4
5	M. Sano, et al., "A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease," New Engl. J. Med., 336(17):1216-22, 24 April 1997. [6 U.S. institutions] *WV332	23	†
6	R.I. Connor, et al., "Change in coreceptor use correlates with disease progression in HIV-1-infected individuals," J. Exp. Med., 185(4):621-8, 17 February 1997. [Aaron Diamond AIDS Res. Ctr.; Rockefeller U., New York, NY] *WK038	22	†
7	P.M. Ridker, et al., "Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men," New Engl. J. Med., 336(14):973-9, 3 April 1997. [Harvard Medical Sch., Boston, MA; Harvard Sch. Public Health, Boston; Brigham and Women’s Hosp., Boston, MA; U. Vermont, Burlington] *WR385	21	†
8	B. Pitt, et al., "Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE)," The Lancet, 349(9054):747-52, 15 March 1997. [7 institutions worldwide] *WN124	21	†
9	H.M. Connolly, et al., "Valvular heart disease associated with fenfluramine-phentermine," New Engl. J. Med., 337(9):581-8, 28 August 1997. [Mayo Clin. & Fdn., Rochester, MN; Meritcare Med. Ctr., Fargo, ND] *XT394	21	†
10	J.W. Mellors, et al., "Plasma viral load and CD4⁺ lymphocytes as prognostic markers of HIV-1 infection," Ann. Int. Med., 126(12):946-54, 15 June 1997. [7 U.S. institutions] *XE549	21	5

SOURCE: ISI's Hot Papers Database. Read the full legend.

The paper chosen from the Top Ten this time could be said to have had its impact a few weeks before publication. Unusually, the New England Journal of Medicine (NEJM) permitted urgent release of the information in paper #9 because of its importance to public health. The ideal drug against obesity would have to achieve significant and sustainable weight loss and do so safely, and the search for this ideal has been unsuccessful. In the 1960s a drug widely used in Europe (aminorex) was withdrawn because of a possible association with pulmonary hypertension, a serious complication; later came reports of a similar association for fenfluramine.

In January of 1997, a physician from Fargo, North Dakota asked the Mayo Clinic if they knew anything about heart-valve problems in patients taking fenfluramine plus phentermine. The clinic had had similar cases, and the outcome is paper #9. That case series plus other evidence, much of it published in the same issue of NEJM, led to the immediate withdrawal of the drugs from the market. The drug combination had never been officially recognized by the U.S. Food and Drug Administration, but "fen-phen," as it was popularly known, was very widely prescribed.

End of story, you might think, and not an obvious source for prolific research citation. Let us now jump forward a year. In its issue of September 12, 1998, NEJM carried three more items and another editorial on the same drug combination. The problem was that although the 1997 evidence had been sufficient for manufacturers and drug regulators, firm proof of causation was still missing. Could obesity itself rather than the drugs have been the problem and, if the drug(s) were to blame, was it "fen" or "phen" or both? A further complication was that fenfluramine was available both as the racemic mixture and as the dextrorotatory dexfenfluramine.

Epidemiological evidence has suggested that obesity itself can be ruled out, and the 1998 studies do point to (dex)fenfluramine as the likely culprit. Now surely that is the end of the matter? Not so. At a 1998 meeting in Paris a few days before the latest round of studies was published, new but conflicting evidence was presented. Nonetheless, the drug or drug combination is unlikely to be rescued now and physicians can concentrate on the practical consequences. The drugs are no longer prescribed, and the concern was largely about potentially serious but presymptomatic valve abnormalities rather than actual heart-valve incompetence; furthermore there is a hint that the abnormality may be reversible (see L.B. Cannistra, A.J. Cannistra, New Engl. J. Med., 339:771, 1998). Dr. Richard B. Devereux (in NEJM) recommends a clinical examination for any patient who has taken the combination, followed by echocardiography if the physician is suspicious and prophylaxis againts endocarditis where indicated.

The frequency of echocardiographically detected valve abnormality in some of the early papers sounds alarming (20-30%) but, as Dr. Devereux points out, quantitative agreement between the studies is not strong. Dr. Hershel Jick and colleagues, from Lexington, Massachusetts but using a U.K. family-practice database that covers about 1 in 15 of the population, found 11 cases of newly identified valve disorder. The five-year cumulative incidence was 3.5 per 1,000 in those taking fenfluramine or its d-isomer for four months or more.

To focus on publishing events in 1998 is not to disparage the importance of the 1997 work. Quite the contrary—epidemiologically more rigorous tools and well-deserved citations have confirmed the continuing importance of original clinical observations to medicine.

Mr. David W. Sharp, MA (Cambridge), is Deputy Editor of The Lancet, London, U.K.