A Drug Half as Good as Ozempic for One-30th the Price
New obesity drugs are remarkable. But few people realize how useful the old ones can be.
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“In my lifetime, I never dreamed that we would be talking about medicines that are providing hope for people like me,” Oprah Winfrey says at the top of her recent prime-time special on obesity. The program, called Shame, Blame and the Weight Loss Revolution, is very clear on which medicines she means. At one point, Oprah stares into the camera and carefully pronounces their brand names for the audience: “Ozempic and Wegovy,” she says. “Mounjaro and Zepbound.” The class of drugs to which these four belong, called GLP-1 receptor agonists, is the reason for the special.
For a brief and telling moment, though, Oprah’s story of the revolution falters. It happens midway through the program, when she’s just brought on two obesity doctors, W. Scott Butsch and Amanda Velazquez, to talk about the GLP-1 wonder drugs. “Were you all surprised in your practices when people started losing weight?” she asks. Butsch gets a little tongue-tied: “Yeah, I mean, I think we have—we’ve already been using other medications for the last 10, 20 years,” he says. “But these were just a little bit more effective.”
Oprah is nonplussed. She didn’t know about these other drugs, before Ozempic, that were already helping people with obesity. “Where was I?” she cries. “Where was the announcement?” Velazquez milks the moment for a laugh—“We didn’t have TikTok; that was our problem,” she says—and the show moves on. Whatever the identity of these medicines that came before, these almost-as-effective ones, they will not receive another mention. The show proceeds as if they don’t exist.
And yet: They do. Amid the hype around the GLP-1s, with their multibillion-dollar sales and corresponding reputation as a modern miracle of medicine, a sort of pharmaco-amnesia has taken hold across America. Patients and physicians alike have forgotten, if indeed they ever knew, that the agents of the “weight-loss revolution”—Ozempic and Wegovy, Mounjaro and Zepbound—are just the latest medications for obesity. And that older drugs—among them Qsymia, Orlistat, and Contrave—are still available. Indeed, the best of these latter treatments might produce, on average, one-half the benefit you’d get from using GLP-1s in terms of weight loss, at less than one-30th the price.
That result should not be ignored. Given the lack of widespread insurance coverage for the newer drugs, as well as marked lapses in supplies, many people have been left out of Oprah’s revolution. For last week’s special, she interviewed a mother and her daughter who say, to pursed-lipped expressions of concern, that they’d love to be on a drug like Wegovy or Zepbound, but “cannot access it financially.” Although the Centers for Medicare and Medicaid Services has just announced that GLP-1 drugs for obesity may now be covered for seniors who also have cardiovascular disease, insurers have been pulling back. Next week, the North Carolina state workers’ health plan will cut off GLP-1 coverage for close to 25,000 people. Other, older drugs could help curb this crisis.
The newer drugs are much more potent. Semaglutide, the active ingredient in Ozempic and Wegovy, produced an additional 12 percent loss of body weight, on average, compared with placebos in clinical trials; the equivalent result for the highest dose of tirzepatide, which is in Mounjaro and Zepbound, was 18 percent. Meanwhile, the most popular of the older drugs for treating obesity, an amphetamine derivative called phentermine, has been shown to produce, on average, a 3 or 4 percent loss of total body weight. When phentermine is prescribed along with another older drug called topiramate—they’re sold in combination as Qsymia—the effect is stronger: more than 9 percent additional weight loss as compared with placebo, according to one trial.
The newer drugs have also been investigated in very large numbers of patients and been shown to measurably reduce obesity-related complications such as strokes, heart attacks, and death. “We have all this data showing that GLP-1 drugs are reducing cardiovascular events and having other benefits,” Eduardo Grunvald, the medical director of the weight-management program at UC San Diego Health, told me, “and we have no data on the other drugs on those issues.” (Like many prominent obesity doctors, including Butsch and Velazquez, Grunvald has received thousands of dollars in consulting fees and honoraria from the maker of Wegovy. He has also received payments from the company behind Contrave.) All else being equal, the GLP-1s are the better option.
But all else is rarely equal. For one thing, the average weight-loss effects reported in the literature can’t tell you how each specific patient will respond to treatment. When people take Wegovy or Zepbound, more than half of them are strong responders, according to the published research, with weight loss that amounts to more than 15 percent. At the same time, roughly one in seven people gets no clear benefit at all. The older drugs also have a diversity of outcomes. Qsymia doesn’t seem to work for about one-third of those who take it, but another third finds Ozempesque success, losing at least 15 percent of body weight. “I’ve had patients who have lost as much or more weight with Qsymia as they do with GLP-1s,” Grunvald said. “It’s about finding that lock and key for a particular individual.”
Depending on that fit, a patient may end up saving quite a bit of money. Since 2016, Sarah Ro, a primary-care physician based in Hillsborough, North Carolina, has run a weight-management program that serves rural communities. She’s been treating patients with the older drugs, she told me, and getting good results: “I regularly have people losing 50 pounds on phentermine alone, or phentermine-topiramate.” These drugs are generally covered by insurance, but Ro prescribes them as generics that are cheap enough to pay for out of pocket either way. “It’s like 10 to 11 bucks for phentermine, and 12 bucks for topiramate,” she said. A similar month’s supply of Wegovy or Zepbound injections is listed at more than $1,000.
“I have to be honest with you, the whole craze and wave of uptake of the GLP-1 medications was a little bit of a surprise to me,” Grunvald said. “We had this decade of drugs that were actually effective, but people really didn’t latch onto them.” Again, he emphasized the obvious fact that the GLP-1 medications work much better, overall, than the old ones. But he and other experts with whom I spoke suggested that the higher potency alone cannot explain an utter turnabout in patient demand, from nearly zero to almost unmanageable.
Several noted that the older drugs are “stigmatized,” as Grunvald put it. In particular, a lot of people are wary of phentermine, on account of its status as an amphetamine derivative, and also its connection to the “fen-phen” scandal of the 1990s, when it was sold as part of an enormously popular (and effective) drug combination that turned out to have dangerous effects on people’s hearts. But as David Saxon of the University of Colorado’s Anschutz Medical Campus explained to me, the problems with fen-phen derived from the “fen” and not the “phen”—which is to say, a different drug called fenfluramine. “Phen,” for its part, has been prescribed as a weight-loss drug for more than half a century—far longer than any GLP-1 agonist has been on the market—and has shown no clear signs of causing serious problems. Its known side effects are similar to those of Adderall, a drug that is now used by more than 40 million Americans.
Topiramate brings other risks, including birth defects, tingling sensations, and changes in mood. Especially at higher doses, it can lead to brain fog. But again, the specifics here will vary from one patient to the next. And GLP-1s have their own side effects, most notably gastrointestinal distress that can be quite unpleasant. About one-sixth of people taking semaglutide are forced to stop; a guest on Oprah’s special said she had to quit after ending up in the emergency room, vomiting blood. Some of these patients may do just fine on phentermine or topiramate. “Honestly, I see more side effects with the GLP-1 drugs than with the other drugs,” Grunvald told me. “I get more messages and phone calls about side effects than I used to.”
Some of the older drugs’ peculiar side effects can even wind up being useful, Ro suggested. Many of her patients with obesity are fond of Mountain Dew, she told me; some are drinking two liters every day. She counsels cutting back on sugary beverages, but topiramate can really help, because it can distort the taste of carbonation. In the clinical literature, this dysgeusia is deemed unwanted—it’s called a “taste perversion.” For Ro, it can be a tool for weaning off unhealthy habits. “We have such a wonderful response to using topiramate,” she said.
Now she’s girding for the change in North Carolina’s health-insurance coverage for state workers. She tells her patients not to panic; if they can’t afford to pay for Wegovy or Zepbound out of pocket, she can switch them to different agents. “Everybody’s talking about GLP-1s, and it’s like, ‘GLP-1s or bust,’” she said. “And I’m going, ‘Hello! You know, my patients never had that much access to GLP-1s anyway.’” Those patients may not end up getting the best possible treatments for obesity—add this to the running list of health disparities—but they can have a drug that works. For anyone who is living with meaningful complications of obesity, having some weight loss will likely be better than having none at all.
If Oprah never got the memo, the problem may have less to do with medicine than with expectation. The older drugs can work, but their average effects on body weight are in the range of 5 to 10 percent, which is about what some people can expect to achieve through major changes to their lifestyle. “Remember, you’re fighting against the cultural current that says, ‘What, you’re taking one of those medicines? That’s awful! You ought to be able to do that yourself,’” Ted Kyle, a pharmacist and an obesity-policy consultant, told me. “The efficacy is not enough to get you over that hump of cultural resistance, and of the stigma attached to taking medicines for obesity.” And then, when a patient on an older drug has reached their new plateau for body weight, which could be just 10 pounds less than where they were before, they may not be so inclined to keep up with their prescription. Are they really going to stay on a medication for the rest of their life, if its effects are not utterly transformative?
Again, it all depends on who you are. Just like the drugs, lifestyle interventions must be used indefinitely, and just like the drugs, they may work out great for certain patients and be of little help to others. “There are some people who get a response to a diet that is comparable to bariatric surgery,” Kyle told me. “It’s just not many of them. And it takes a really smart provider of obesity care to say, ‘You know what, I’m going to work with you to get you to your best possible outcomes.’” (Many primary-care doctors simply aren’t trained in how to use the older drugs, Ro said.) If we aren’t ready to give up on recommending healthy diets and more exercise, then let’s not forget the other options. These drugs work. The weight-loss revolution didn’t start in 2021.