Fen-Phen and Medication Mistrust

October 29, 2021

October 2021 Letter from the Director

Despite the promise of increasingly effective pharmacotherapy for obesity, the rate of prescriptions for weight-loss medications in the US is surprisingly low. A study of over 2.2 million adults from 2009 to 2015 found that the rates of rates of prescriptions for anti-obesity medications (AOMs) ranged from 0.6% to 2.9% of eligible patients. The study results also demonstrated an uneven distribution of these prescriptions. Of those providers who prescribed AOMs, the majority (72.9%) prescribed them to five or fewer patients, and only a small proportion (8.3%) of providers prescribed to 21 or more patients. The prescribers who wrote the most prescriptions wrote 89.6% of all filled prescriptions in the study.

The low rate of prescriptions of AOMs may date to the early history of obesity treatment with pharmacotherapy. In the early to mid-1990s, FDA approved three drugs -- phentermine, fenfluramine, and dexfenfluramine -- to treat obesity. In particular, providers began to prescribe a combination known as “fen-phen,” with the “fen” referring to fenfluramine or dexfenfluramine and the “phen” referring to phentermine. In 1996, doctors wrote a total of 18 million monthly prescriptions for either fenfluramine or phentermine. By 1997, however, the trend of providers prescribing this drug combination ended abruptly when multiple cases of adverse events were recorded. Clinicians identified cases of valvular heart disease and unusual valvular morphology in 24 women treated with the combination of fenfluramine-phentermine for an average of 12 months.

Following these adverse events, the FDA issued a public health advisory for fen-phen and requested that health care providers send in patient information on any effects from taking the combination of drugs. The FDA received information on 113 cases in addition to the original 24 publicly reported cases; according to a CDC MMWR report, “Of these 113 cases, two (2%) used fenfluramine alone; 16 (14%), dexfenfluramine alone; 89 (79%), a combination of fenfluramine and phentermine; and six (5%), a combination of all three drugs. None of the cases used phentermine alone.” Further studies demonstrated an association between fen-phen use and increased risk of cardiac-valve regurgitation and pulmonary hypertension, especially if the drugs were taken for more than three months. A likely mechanism that could account for how fenfluramine and dexfenfluramine contribute to these cardiac conditions is that they may target serotonin receptors on heart valves, leading to fibrosis. As a result of these findings, fenfluramine and dexfenfluramine were voluntarily taken off of the market.

The adverse effects of these drugs recognized 25 years ago may have established a lasting sense of mistrust among providers when it comes to obesity medications. A recent survey of providers found that only 4% of primary care physicians (PCPs) felt that weight loss medications were safe, whereas 60% of PCPs reported that a concern of adverse events was a barrier to prescribing these medications. The survey also found that 76% of all PCPs did not prescribe weight loss medications for long-term weight loss therapy, and over half (58%) of PCPs reported “negative” and “very negative” perceptions of pharmacotherapy as a treatment for obesity.

In analyses that STOP published from the 2016 and 2017 Docstyles surveys, 31% of healthcare providers said they did not prescribe drug therapy for obesity, and only 8% of healthcare providers surveyed could correctly identify the guideline-recommended thresholds to initiate and continue pharmacotherapy for obesity. Earlier data from 2009-2015 suggest that the rates of obesity medications reportedly prescribed by respondents to the Docstyles surveys are overestimates.

Despite the problematic past of some obesity medications, many important advances have been made in the field of pharmacotherapy. New medications such as semaglutide have proven safe and effective, with a low incidence of severe side effects. Nonetheless, many providers still believe that obesity medications are unsafe, despite substantial research that has proven otherwise. Moving forward, it is important that providers are educated about the safe and effective treatments for obesity that are available.