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  • Ozempic Can Turn Into No-zempic

    Ozempic Can Turn Into No-zempic

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    No medication in the history of modern weight loss has inspired as much awe as the latest class of obesity drugs. Wegovy and Zepbound are so effective that they are often likened to “magic” and “miracles.” Indeed, the weekly injections, which belong to a broader class known as GLP-1s, can lead to weight loss of 20 percent or more, fueling hype about a future in which many more millions of Americans take them. Major food companies including Nestlé and Conagra are considering tailoring their products to suit GLP-1 users. Underlying all this excitement is a huge assumption: They work for everyone.

    But for a lot of people, they just don’t. Anita, who lives in Arizona, told me she “took it for granted” that she would lose weight on a GLP-1 drug because “the people around me who were on it were just dropping weight like mad.” Instead, she didn’t shed any pounds. Likewise, Kathryn, from Florida, hasn’t lost any weight since starting the medication in October. “I was really hoping this was something that would be a game changer for me, but it feels like it was just a lot of wasted money,” she told me. (I’m identifying both Anita and Kathryn by their first name only to allow them to speak openly about their health issues.)

    Some people can’t tolerate the side effects of the drugs and have to stop taking them. Others simply don’t respond. For some, the strength of the dose, or length of the treatment, does not seem to make a difference. Appetites might remain robust; the “food chatter” in the brain may stay noisy. Together, both groups of less successful GLP-1 users account for a not-insignificant share of patients on these drugs—potentially up to a third. “We don’t really know why it happens, [but] we know it does happen,” Louis Aronne, an obesity-medicine specialist at Weill Cornell Medical College, told me. Despite the promise of a so-called Ozempic revolution, lots of “No-zempics” have been left behind.

    Of the two biggest reasons some people don’t lose weight on GLP-1 drugs—side effects and nonresponse—the former is much more straightforward. The GLP-1 drugs Wegovy and Zepbound (which contain the active ingredients semaglutide and tirzepatide, respectively), are known for causing potentially gnarly gastrointestinal symptoms, such as nausea and vomiting, although most people’s reactions are mild and temporary. Yet some have it far worse. Severe, albeit uncommon, side effects include pancreatitis, severe gastrointestinal distress, low blood sugar, and even hair loss, which “can push people off” the drugs, Steven Heymsfield, a professor who studies obesity at Louisiana State University, told me. In one of the biggest studies of semaglutide, encompassing more than 17,000 people over about five years, nearly 17 percent of patients discontinued the medication because of side effects.

    Far more mysterious are the people who tolerate the drugs but respond weakly to them—or sometimes not at all. Researchers have known this might happen since these drugs were in early clinical trials. About 14 percent of people who took semaglutide for obesity saw minimal impacts of less than 5 percent weight loss in one study, as did 9 to 15 percent of people who took tirzepatide in a similar one. In her own experience working with patients, “somewhere between a quarter and a third” are nonresponders, Fatima Cody Stanford, an obesity-medicine specialist at Harvard, told me, adding that it can take up to three months to determine whether the drug is working or not. That the same medication at the same dosage can lead to dramatic weight loss in one person and hardly any in another “remains confounding,” Aronne told me.

    The broad explanation is that it has something to do with genetics. The drugs work by masquerading as the appetite-suppressing hormone GLP-1 and binding to its receptor, like a key fitting into a lock. Although the lock’s overall shape is generally consistent from person to person, its nooks and crannies can vary because of genetic differences. “For some people, that key just won’t fit right,” Eduardo Grunvald, an obesity-medicine doctor at UC San Diego Health, told me. In other cases, genes may limit the effects of these drugs after they bind to GLP-1 receptors. One possibility is that people metabolize the drugs differently: Some patients may break them down too quickly for them to take effect; others may process them too slowly, potentially building up such high levels of the medications that they become toxic, Heymsfield said.

    For No-zempic patients, perhaps the most consequential impact of individual variation is on the propensity for obesity itself. “We are all very different from a genetic standpoint, in terms of our risk of weight gain,” Grunvald said. Numerous factors can drive obesity, including diet, environment, stress, and—most pertinent to GLP-1 drugs—altered brain function.

    GLP-1 drugs target a pathway that regulates appetite and insulin levels. Some cases of obesity can be caused by a disruption in that particular mechanism, in which case GLP-1s can indeed be wondrous. But “not everyone has dysfunction in this particular pathway,” Stanford said. When that is the case, the drugs won’t be very effective. A different pathway, for example, controls the absorption of fat from food; another increases energy expenditure. In these people, GLP-1s might tamp down appetite to a degree, maybe leading to some weight loss, but a different drug may be required to treat obesity at its root. “It is not all about food intake,” Stanford said.

    That’s not to say that No-zempics are out of options. They might have better success switching from one GLP-1 to the other, or even stacking them, Heymsfield said. Some patients who don’t respond to GLP-1s at all can get better results with older drugs that work on different obesity pathways, Aronne said. One, called Qysmia, a combination of the decades-old drugs phentermine and topiramate, can lead to an average weight loss of 14 percent body weight at its highest dose. If medications don’t work, bariatric surgery remains a powerful option, one that may even be growing in popularity. Last year, the number of bariatric surgeries performed in the U.S. grew despite the boom in GLP-1 usage, a trend that some expect to continue, because so many people don’t tolerate the drugs.

    The intense hype around the game-changing nature of GLP-1s makes it easy to forget that they are, in fact, just drugs. “Every drug that’s ever been made” works in some people and not in others, Heymsfield said; there’s no reason to think GLP-1s would be any different. Remembering that they are in an early stage of development has a sobering effect. Eventually, obesity drugs may leave fewer people behind. The category is expanding rapidly: By one count, more than 90 new drug candidates are in development.

    They are evolving to attack obesity from multiple fronts, which, at least in theory, widens their net of potential users. In an early study on an experimental candidate named retatrutide—called a triple agonist because it acts on GLP-1 as well as two other targets involved in obesity, GIP and glucagon receptors—100 percent of people on the highest dose lost 5 percent or more of their body weight. New candidates are also expected to have fewer side effects. They have to, Heymsfield said, because the competition is so steep that any new drug has to be “as good with less side effects, or better.”

    But no matter how good these drugs get, it’s unrealistic to think that they’ll become a one-size-fits-all treatment for everyone with obesity. The disease is simply too complex, with too many drivers, for a single type of medication to treat it. More than 200 different drugs exist for treating high blood pressure alone; in comparison, Aronne said, regulating weight is “far more complicated.” The future, rife with options, holds promise that No-zempics may find a way forward. Yet considering all the unknowns about obesity and what causes it, that may not be enough to guarantee that they will see the results they want.

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    Yasmin Tayag

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  • Ozempic Is About to Be Old News

    Ozempic Is About to Be Old News

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    All of a sudden, Ozempic is everywhere. The weight-loss drug that it contains, semaglutide, is a potent treatment for obesity, and Hollywood and TikTok celebrities have turned it into a sensation. In just a few months, the medication has been branded as “revolutionary” and “game-changing,” with the power to permanently alter society’s conceptions of fatness and thinness. Certainly, a drug like semaglutide could be all of those things: Never in the history of medicine has one so safely led to such dramatic weight loss in so many people.

    But let’s not get ahead of ourselves. As weight-loss medications go, Ozempic is far from perfect. Though the drug has profound impacts, it requires weekly injections, a tolerance for uncomfortable side effects, and the stamina—not to mention the budget—for long-term treatment. (Ozempic has somehow become a catchall term for semaglutide but technically that product has gotten FDA sign-off only as a diabetes medication. A larger dose of semaglutide, marketed as Wegovy, has been approved for weight loss.)

    Made by the Danish drugmaker Novo Nordisk, semaglutide dominates the U.S. weight-loss market right now, but its reign might be short-lived. The colossal demand for these drugs has spurred a competition in the pharmaceutical industry to develop even more potent and powerful medications. The first of them could become available as soon as this summer. For all its hype, semaglutide is the stepping stone and not the final destination of a new class of obesity drugs. Just how good they get, and how quickly, will go a long way in determining whether this pharmaceutical revolution actually meets its full promise.

    In a sense, semaglutide hardly represents a major step forward in science. Diet drugs are nothing new, and even the category of pharmaceuticals that these new products belong to, called “GLP-1 agonists,” has been around for several years. These drugs mimic the hormone GLP-1 (glucagon-like peptide one) and bind to its receptor in the body. This triggers a sense of fullness associated with having just eaten, and also slows the release of food from the stomach. (It also increases insulin secretion, keeping blood sugar in check, which is why Ozempic is still intended as a diabetes drug.) Already, these pharmaceuticals have gotten better over time: A daily injection called liraglutide and sold as Saxenda, which was approved by the FDA in 2014 for obesity, leads to the loss of 5 to 10 percent of a person’s body weight in most cases. But one reason semaglutide took off in a way that liraglutide didn’t is that it can lead to weight loss of up to 20 percent. “Now you have a shot that’s once a week instead of every day, you’re making dramatic improvements, and people notice more,” Angela Fitch, the president of the Obesity Medicine Association and the chief medical officer of the obesity-care start-up Knownwell, told me.

    But not everyone who takes these drugs can achieve that level of weight loss. More than 60 percent of those on Wegovy experience smaller changes, in part because the drug can’t account for the complex drivers of obesity that aren’t related to food. The next generation of drugs is reaching for more. The first leap forward is Mounjaro, known generically as tirzepatide, a diabetes drug from Eli Lilly that the FDA is expected to approve for weight loss this year. In one study, it led to 20 percent or more weight loss in up to 57 percent of people who took the highest dose; The Wall Street Journal recently called it the “King Kong” of weight-loss drugs. People on Mounjaro tend to lose more weight more quickly and generally have a “better experience” than those on Wegovy, Keith Tapper, a biotech analyst at BMO Capital Markets, told me. It’s also cheaper, though by no means cheap, at roughly $980 for the highest-dose option, he said; a dose of Wegovy costs about $1,350.

    These leaps in potency are happening on the molecular level. Like semaglutide, Mounjaro mimics the effects of GLP-1, but it also hits receptors for another hormone—GIP. That leads to even more weight loss by further attenuating focus on food and potentially also increasing the activity of a fat-burning enzyme, said Tapper. So-called dual-agonist drugs “offer a step change” in both weight loss and blood-sugar control, he added.

    And why stop at two receptors when so many others are involved in regulating hunger? “This area is exploding in terms of research and testing different combinations of hormones,” which are still poorly understood, Shauna Levy, a professor specializing in bariatric surgery at Tulane University School of Medicine, told me. Eli Lilly has another drug in the works that targets three receptors; one from the drugmaker Amgen works by “putting the brakes” on the GIP receptor and “putting the gas” on GLP-1’s, a company spokesperson told me. Several other companies have already joined what some have dubbed a “race” to develop the next great obesity drug, in which Lilly, Pfizer, Amgen, Structure Therapeutics, and Viking Therapeutics are expected to be the front-runners, said Tapper.

    The potency of weight-less drugs is not the only factor that will determine the shape of their future trajectory. Wegovy and Mounjaro injections are tolerable for most people, but they are less convenient than a pill. Making oral versions of these drugs isn’t as easy as packing everything into a capsule, though. Semaglutide is a molecule that gets chewed up in the stomach. For this reason, the semaglutide pill Rybelsus, which is already approved for diabetes, leads to far less dramatic weight loss than its injectable kin. But drugmakers are undeterred by this complication, because a pill even more powerful than semaglutide would no doubt have many customers. In January, Pfizer’s CEO Albert Bourla said that an oral weight-loss drug “unlocks the market,” which he estimated could eventually be worth $90 billion. Pfizer doesn’t have any weight-loss drugs yet but is developing a twice-daily GLP-1 agonist pill; Eli Lilly also has an oral version in the works. Tapper expects those drugs to become available in 2026, and a similar offering from Structure Therapeutics is likely to follow the next year.

    Drugmakers will also likely vie to create drugs with fewer side effects. Novo Nordisk notes that gastrointestinal issues are common with semaglutide; accounts of horrible nausea, constipation, and vomiting have proliferated online. As one actor put it to New York Magazine, people on Ozempic are “shitting their brains out.” With Wegovy, more serious issues, such as pancreatitis, thyroid cancer, and kidney failure, are also possible but are considered rare. Although nothing to scoff at, side effects tend to subside with prolonged treatment and can usually be managed with help from a doctor, said both Fitch and Levy, who regularly prescribe semaglutide to patients with obesity. It’s possible, Levy added, that people experiencing really terrible effects may be getting their drugs from shady compounding pharmacies or even from other countries.

    The fact that people are turning to sketchy outlets to get weight-loss drugs underscores the biggest issue with them: access. Medicare and most private insurance companies don’t cover anti-obesity drugs. (Such drugs are classified as “cosmetic” by the Centers for Medicare and Medicaid Services, and thus don’t qualify for coverage.) “I am hopeful that the price will come down with more competition,” Fitch told me. But there’s no guarantee that will happen: Competition typically makes a product cheaper over time, but research suggests that isn’t always the case in pharmaceuticals. Even if the drugs do become cheaper, they may not become cheap enough. The oral forms of these drugs, some of which could be available by 2026, are expected to cost about $500 a month, Tapper said. By 2030, the cost of obesity drugs could come down to about $350 a month, according to a recent Morgan Stanley analysis, which would still be out of reach for many Americans.

    Levy estimates that the next five years will bring about a “huge explosion” of next-gen obesity drugs. In that case, the market will likely expand to accommodate a variety of drugs with different price points and efficacies. Some people may aim to lose 20 or more percent of their body weight; some may be content with less. The market is so diverse that it will likely “support a broad range of options,” said Tapper, such as cheaper, lower-dose oral drugs for people who have milder medical issues, and more expensive injectables for those with more severe medical concerns. That opens up the possibility that medically mediated weight loss could soon be an option for a far greater proportion of people.

    Regardless of how much these drugs’ costs may decrease, they will always add up if people are paying out of pocket for them. They are meant to be taken long term: Once a person stops taking Wegovy, the weight tends to come right back. The current crop of weight-loss medications are essentially maintenance drugs, much like the cholesterol-busting drug Lipitor, which is taken daily to treat long-term disease. But Lipitor, unlike obesity drugs, is generally covered by insurance. Unless obesity drugs receive the same kind of coverage, no level of improvement will lead them to deliver on what Ozempic is promising us now.

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    Yasmin Tayag

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