Fen-Phen Again? Why Ozempic and New Weight-Loss Drugs Are Different

The drug Ozempic, after just a few years on the market, has already become a household name synonymous with weight loss. The popularity of it and similar medications has skyrocketed so immensely and rapidly that one drugmaker ran commercials telling people to stop using the products if they’re only looking to drop a few pounds.

It’s clear that these drugs actually work, helping people with obesity lose far more weight on average than diet and exercise alone. And every week seems to bring new findings on other potential benefits, such as helping prevent cardiovascular disease or treating drug addiction.

But for some people, Ozempic and its ilk are simply the latest iteration of a well-worn cautionary tale: too-good-to-be-true weight loss aids that will inevitably prove to be dangerous and even deadly. Perhaps the most infamous example is the drug combination fen-phen, which was taken off the market in the late 1990s after it was found to raise the risk of severe, even life-threatening heart problems. While there are enduring lessons to be learned from the saga of fen-phen, there are also several important differences between it and the newest generation of obesity drugs.

Fen-phen is short for the drugs fenfluramine and phentermine. Both are appetite suppressants, but they work in different ways. Fenfluramine increases levels of serotonin, while phentermine primarily increases levels of norepinephrine—two neurotransmitters that have many important roles, including the regulation of appetite.

Starting in the 1950s, the drugs were separately approved as short-term (a few weeks) obesity treatments. But on their own, they only seemed to help people lose a bit more weight than they would normally and came with plenty of irritating side-effects like dizziness, dry mouth, and trouble sleeping. In 1979, Michael Weintraub, then a professor of clinical pharmacology at the University of Rochester, had the idea of combining the two, reasoning that since the drugs affected the body differently to suppress appetite, they might have an even greater synergistic reaction that could also limit side-effects by requiring a lower dose.

Weintraub’s work testing fen-phen on his obese patients appeared to confirm the theory, showing that people taking the combo lost more weight and maintained more weight loss than those on placebo, for up to four years and seemingly with no major adverse effects. It would take until 1992 for most of this research to be published. Once it was, other doctors soon adopted fen-phen as their obesity treatment of choice.

By the mid-1990s, as many as 18 million prescriptions for the two drugs were being doled out annually. In 1996, the makers of fenfluramine, American Home Products, received approval from the Food and Drug Administration for a slightly different version of the drug, called dexfenfluramine and sold under the name Redux, which also quickly became paired with phentermine. Redux was ostensibly an improvement over the original, though the approval would also cushion the company’s impending loss of its exclusivity over fenfluramine. The very next year, however, these plans came to an abrupt halt.

In early 1997, 30-year-old Massachusetts resident Mary Linnen died from complications of pulmonary hypertension—complications that her family alleged were caused by her taking fen-phen for only three weeks. Later that summer, doctors from the Mayo Clinic published a paper finding a link between fen-phen use in their patients and the emergence of heart valve disease as well as pulmonary hypertension. Five of their patients needed valve repair surgery.

Pulmonary hypertension, or high blood pressure in the arteries connecting the heart to the lungs, had previously been documented as a potential rare side-effect of fenfluramine and similar drugs, but the uncovering of the heart valve risk was new. By that September, at the FDA’s request, American Home Products pulled both fenfluramine and dexfenfluramine off the market.

The root cause of these issues was the increased levels of circulating serotonin brought on by fenfluramine, which can be damaging to blood vessels and heart valves. Some research has also suggested that the addition of phentermine might have contributed by increasing serotonin levels in a different way, though not to the same extent as fenfluramine. That said, phentermine alone has never been linked to either complication, nor was it ever recalled as an obesity treatment.

There’s limited data on just how many people might have been harmed by fen-phen. But a 2000 study of over 1,000 patients found that 8.8% who took the drug combo were later diagnosed with at least mild heart valve disease, compared to 3.6% of a control group, with this risk going up the longer that they were on the medication. And following the recall of its drugs, American Home Products would pay billions to settle lawsuits brought against it by thousands of former fen-phen patients, including the family of Mary Linnen.

As serious as the crisis caused by fen-phen was, though, there’s only so much that the drug combo has in common with the newest obesity medications on the market, Novo Nordisk’s semaglutide and Eli Lilly’s tirzepatide. For starters, the treatments work differently: Semaglutide and tirzepatide are part of a class of drugs known as incretins, which mimic hormones important to regulating our hunger and metabolism. This drug class has long been used to manage type 2 diabetes by helping safely boost insulin production that can keep high blood sugar in check, with the first product of its kind (exenatide) approved in 2005.

Over time, scientists have been able to create longer-lasting mimics of these hormones, leading to the development of once-weekly semaglutide and tirzepatide. Semaglutide mimics GLP-1, while tirzepatide mimics GLP-1 and the hormone GIP. Both drugs were originally approved for type 2 diabetes and later as an obesity treatment, with semaglutide sold under the names Ozempic and Wegovy, and tirzepatide under the names Mounjaro and Zepbound.

The cells that respond to these hormones are found both in the gut and brain. Incretins are thought to tamp down appetite not only by physically affecting the digestive tract, such as by slowing digestion, but by interacting with these brain cells. The net result is that people need to eat less food to feel full and feel less cravings for food in general.

Another difference between fen-phen and incretins is how these products reached the public. While the halves of fen-phen were approved separately for obesity, the drug combination itself never was, with doctors prescribing it off-label. This meant that fen-phen never underwent the extensive clinical trial process that most drugs on the market today, including semaglutide and tirzepatide, did. The original 1992 trial that sparked fen-phen’s popularity involved 121 patients; by contrast, the Phase III clinical trials of semaglutide and tirzepatide for obesity have involved thousands of patients each, as did the trials for type 2 diabetes.

Large-scale clinical trials aren’t the only valid evidence of a drug’s safety, and incretins certainly have their own side effects. They’re known to commonly cause gastrointestinal symptoms like nausea, vomiting, and diarrhea, for example, though these symptoms seem to wane over time. But we simply have a lot more data on these drugs than we ever did on fen-phen, dating all the way back to the earliest GLP-1s in the mid-2000s. And currently, the data is firmly in their favor.

Studies have not only found that the newest drugs reliably help obese people lose substantial weight (15% to over 20% body weight over a year’s time), but they also seem to reduce the risk of heart and kidney problems in people at higher risk for them. Recently, the FDA formally approved Wegovy as a treatment for preventing further heart attacks and strokes in obese people with existing cardiovascular disease. Some early research has also suggested that GLP-1s can reduce cravings related to opioids and alcohol and that they might even have antidepressant effects.

“I think, overall, the benefits on glucose control, body weight, the cardiovascular and the renal protections—they overcome any concern regarding the long-term use of these medicines,” Guillermo Umpierrez, a professor of medicine in the division of endocrinology at Emory University School of Medicine, told Gizmodo.

That isn’t to say that GLP-1s have no drawbacks. Leaving aside the known and often uncomfortable gastro symptoms, there is some speculation, based on animal data, that the drugs could raise the risk of a rare form of thyroid cancer. Though this risk hasn’t been confirmed in human studies—and a recent study of Scandinavians found no evidence for a link—GLP-1s are still not recommended for anyone with a family history of this cancer. And much like fen-phen, we do seem to be discovering new potential side-effects from GLP-1 use following their newfound popularity with the public.

Some patients and doctors have reported likely rare but serious complications such as gastroparesis (stomach paralysis), pancreatitis, and ileus (intestinal blockage) from taking these drugs. Last September, the FDA found the reports credible enough to update its labeling of Wegovy and Ozempic to mention the possible risk of ileus, though it did not confirm it as an established side effect. Health agencies have also started to investigate a possible link between GLP-1 use and increased suicidal ideation, though the FDA reported earlier this year that it has not found strong evidence of this connection, and a large EU investigation came to a similar conclusion. The dramatic weight loss experienced by patients might also cause a large loss of lean muscle, which can raise the risk of other health problems. Though it’s still unclear whether these drugs cause more muscle loss than any form of losing weight would, some pharma companies are already trying to find ways to counteract it.

Not every consequence tied to the emergence of GLP-1s is medical. Production problems and high demand have led to recurring shortages of semaglutide and tirzepatide, with many doctors prescribing the diabetes brands of these drugs off-label for weight loss. As a result, some people with diabetes have been switched to other, possibly less effective drugs.

The lack of supply, poor insurance coverage, and high list prices (over $1,000 a month without coverage) of these drugs has also led to a gray and black market, with compounded and counterfeit versions now prominently advertised. Though these versions might be cheaper upfront, they have no guarantee of safety or effectiveness. Some people have ended up in the hospital from taking products falsely labeled to contain semaglutide, while others who aren’t obese but taking GLP-1s to quickly lose weight might be putting themselves in danger. And some patients who legitimately could be helped by these drugs will not respond to them or won’t be able to tolerate the side effects.

Perhaps the key lesson of the fen-phen crisis is that every approved medical treatment, no matter how miraculous it might seem at first glance, has its risks. Doctors, regulators, and the public all play a part in keeping watch and making sure that the risks of a drug don’t outweigh the benefits for the potential population of patients who take it. Ideally, when this does happen, agencies like the FDA can take action to address it, such as by removing the drug from the market.

“Just like we say to every patient when we’re prescribing medications, there’s nothing that we’ve prescribed that is without the potential for adverse effects. And some of those adverse effects may not yet be described,” Heidi Connolly, a cardiologist at the Mayo Clinic who was one of the first doctors to discover the link between fen-phen and heart valve disease, told Gizmodo. “And so I think it’s very important to be mindful of any medications that are being used and to observe patients for adverse effects.”

This balance between risk and benefit is often complicated, though, and even once-villains like fenfluramine can be redeemed under the right circumstances. While fen was receiving lots of attention for its weight loss effects in the 1990s, some doctors began to notice that it also seemed effective at reducing certain kinds of seizures in children. It would take decades and several clinical trials, but in 2020, the FDA and health regulators in Europe approved a version of fen as a treatment for seizures associated with Dravet syndrome, a rare and severe form of epilepsy that starts early in childhood; in 2022, it was further approved for treating seizures associated with the similar Lennox-Gastaut syndrome.

The drug now comes with a clear warning of its link to heart valve disease and pulmonary hypertension, and children are required to regularly undergo testing to monitor for these complications. But for these patients, who tend to not respond to other drugs, fen has once again become worthwhile. At least for the time being, the same can be said for people taking the latest obesity drugs as intended.