First public report of valvular heart disease in fen-phen users

On July 8, 1997, researchers publicly reported 24 cases of valvular heart disease in women who had been treated with the appetite suppressants fenfluramine and phentermine — the combination known as "fen-phen" ^[1]. Valve lesions appeared on both sides of the heart, but a left-sided valve was affected in every case, and the tissue findings looked like those seen in carcinoid-induced valvular disease, a syndrome linked to serotonin ^[1].

The Food and Drug Administration issued a public health advisory the same day and followed it with letters to 700,000 U.S. health-care practitioners and institutions asking whether they had seen similar patients ^[1]. Reports then climbed quickly.

What the reports showed

By September 30, 1997, the FDA had received 144 individual, provider-initiated reports of valve problems tied to fenfluramine or dexfenfluramine, with or without phentermine — a total that included the original 24 publicly reported cases ^[1]. Of the 132 reports with complete information, 113 (86%) met the agency's case definition, which required documented aortic regurgitation of mild or greater severity and/or mitral regurgitation of moderate or greater severity after exposure ^[1].

Among those 113 cases, 111 (98%) were women, and the median age was 44 years, ranging from 22 to 68 ^[1]. Two patients (2%) had used fenfluramine alone, 16 (14%) dexfenfluramine alone, 89 (79%) the fenfluramine-phentermine combination, and six (5%) all three drugs ^[1]. None had used phentermine alone ^[1]. The median length of drug use was 9 months, ranging from 1 to 39 months ^[1]. Seventy-seven percent had symptoms, 27 patients (24%) needed cardiac valve-replacement surgery, and three of those died after surgery ^[1].

Because valve damage can be silent for a long time, the FDA also looked at five independent, unpublished echocardiographic surveys of people who had taken these drugs but had no obvious cardiac history or symptoms ^[1]. The prevalence of valve disease meeting the case definition ranged from 30.0% to 38.3% across the surveys, with an overall figure of 32.8% (95% confidence interval 27.7%–38.9%) ^[1]. Preliminary population-based studies suggested the expected background rate in adults was 5% or lower ^[1]. Preliminary data also hinted at longer exposure mattering: 22% for less than 3 months of use (5 of 23), 22% for 3–5 months (5 of 23), and 35% for 6 months or more (83 of 236) ^[1].

Notably, a heart murmur could be heard in only 17% of patients who met the case definition, which is why federal officials concluded that history and physical exam alone were not sensitive enough to detect the problem — especially when obesity makes murmurs harder to hear ^[1]. Based on the five surveys, the FDA asked for voluntary withdrawal, and on September 15, 1997, the manufacturers and FDA announced that fenfluramine and dexfenfluramine were off the U.S. market ^[1].

Why it matters for patients

The scale of exposure explains why this became a national health issue rather than a footnote. Since 1995, roughly 14 million prescriptions had been written for fenfluramine or dexfenfluramine, mostly to women and people under 60 — an estimated 1.2 million to 4.7 million Americans ^[1].

The episode also shows how weight-loss drug safety signals can surface after approval and after millions of prescriptions. Phentermine was approved in 1959 for short-term use, fenfluramine (Pondimin) in 1973, and dexfenfluramine (Redux) in 1996 for longer-term use in markedly obese people, with the FDA noting that safety beyond one year had not been established in trials ^[1]. Fen-phen itself was a widely used combination that went beyond the approved short-term single-drug labeling ^[1].

Several things were still unknown at the time: whether the lesions resolve, progress, or stay the same after stopping the drug; what mild valve changes mean in people without symptoms or murmurs; and which patients might be predisposed ^[1]. Federal agencies also flagged a possible risk of bacterial endocarditis after certain invasive procedures in people with left-sided valve disease, citing 1997 American Heart Association prevention recommendations ^[1].

What happens next

In November 1997, the Department of Health and Human Services — working with CDC, FDA and NIH — issued interim recommendations calling for a medical history and cardiovascular examination for everyone exposed to fenfluramine or dexfenfluramine for any length of time, plus echocardiographic evaluation for defined groups, and said the guidance could be revised as better data on the natural history of the disease emerged ^[1].

These sources address only the fenfluramine-era drugs. They do not evaluate today's GLP-1 medicines such as semaglutide or tirzepatide.