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Tag: percent weight loss

  • 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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  • The Ozempic Plateau

    The Ozempic Plateau

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    The latest weight-loss drugs are rightly hailed as game changers for obesity, but in an important way, they are just like every other method of managing weight: They work only to a point for weight loss. The pounds melt off quickly at first and then gradually and then not at all. You can’t lose any more no matter what you do. You’ve hit the weight-loss plateau.

    It happens with dieting. It happens with bariatric surgery. And it happens now with both semaglutide (better known as Ozempic or Wegovy, depending on whether it’s prescribed for diabetes or weight loss) and tirzepatide (better known as Mounjaro or Zepbound). Weight loss triggers a set of powerful physiological changes in the body, which evolved over millions of years to keep us alive through periods of food scarcity. “Everybody plateaus,” says Jamy Ard, an obesity doctor at Wake Forest University. Exactly when varies quite a bit from person to person, but it happens after losing a certain percentage of body weight—meaning some people might plateau while still meeting the criteria for obesity.

    For Wegovy, it’s after losing, on average, 15 percent, usually more than a year into starting the drug. For Zepbound, it’s about 20 percent. These numbers are higher than is sustainable through diet and exercise alone, but they also do not reach the 30 percent achievable via the gold standard of bariatric surgery.

    These differences matter because they suggest that the level of the plateau is not permanently fixed. Recent advances in understanding the gut hormones that these drugs are designed to mimic hint at a possibility of even more powerful weight-loss drugs. Scientists are now testing ways to push the plateau down further; a drug could one day be even more effective than bariatric surgery.

    Read: Ozempic is about to be old news

    All of this raises an unsettled question: “How much weight loss is enough?” says Jonathan Campbell, who studies gut hormones at Duke. In studies, even 5 to 15 percent weight loss can substantially reverse high blood pressure, high blood sugar, and high cholesterol. Yet a patient who starts at 375 pounds with a BMI of 60 might still find themselves ineligible for a joint replacement that requires a BMI below 40, flawed as BMI may be. Or they may simply want to look thinner. The explosion of weight-loss drugs has reopened thorny questions about how they should be used, but nevertheless, pharmaceutical companies are racing ahead to develop more and more powerful ones.

    Weight loss is easiest at the beginning, before your body starts actively working against it. “Your brain doesn’t know you’re trying to lose weight on purpose,” Ard says. And once it notices, “it thinks that something is wrong.” So your body tries very, very hard to compensate.

    First of all, you become hungrier, obviously. And not just because you want to eat as much as you did before; you actually want to eat more than you did prior to losing weight. “With every one kilogram you lose, your appetite goes up above baseline by 90 or so calories per day,” says Kevin Hall, who studies metabolism at the National Institute of Diabetes and Digestive and Kidney Diseases. At the same time, your body looks for ways to conserve energy. Your muscles work more efficiently, for example, Ard says, so walking that normally burned 100 calories might now burn only 90. By making you want to eat more and burning fewer calories, your body is eventually able to slow weight loss down to zero. Here is your plateau. This is, all told, a remarkably elegant and robust system, if what you wanted to do is to maintain your weight.

    If you’re in fact trying to lose more weight, the plateau is psychologically frustrating. The same diet, the same exercise routine, the drug on which you were just losing weight will seem to have stopped working—but they haven’t. (If they did actually stop working, you would be regaining weight.) But your body is now fighting so hard against the weight loss that it requires a persistent effort just to keep the weight off, Hall says. Should you ease up, the weight will come right back, as seen in yo-yo dieting or weight regain after stopping Wegovy or Zepbound.

    The only way to get past a plateau is to up the intensity or number of interventions. Doctors might recommend, for example, bariatric surgery and a weight-loss drug. But in the future, novel drugs might be able to pharmacologically up the intensity. The progression from Wegovy to the more effective Zepbound has in fact already brought us one step closer.

    Wegovy and Zepbound both belong to a class of drugs that mimic a gut hormone called GLP-1. Both of these drugs bind GLP-1 receptors in the brain, which seems to reduce hunger. Zepbound goes a step further, though. It can also bind receptors for a second gut hormone, called GIP. Years ago, researchers noticed that bariatric surgery changes the balance of gut hormones in the body, including GLP-1 and GIP. This—and not just the physical shrinking of the stomach—is now understood to be a key driver of weight loss, to the point that bariatric surgery is sometimes called “metabolic surgery.” These observations inspired research into drugs that target not just GLP-1 but also GIP and other hormones. Essentially, they’re performing metabolic surgery with a drug rather than a scalpel.

    Read: Did scientists accidentally invent an anti-addiction drug?

    Exactly why Zepbound outperforms Wegovy is still unclear. One obvious hypothesis is that it mimics a second gut hormone; the more hormonal pathways it can influence, perhaps, the more body parts it affects and the more weight loss it triggers. And a recent clinical trial of retatrutide, a further modified derivative of Zepbound that mimics a third hormone called glucagon, demonstrated even greater weight loss: 24 percent at the highest dose.

    A second hypothesis suggests that the difference between Wegovy and Zepbound still goes back to GLP-1. Although both drugs bind that receptor, they tickle it slightly differently, setting off slightly different chain reactions. Wegovy seems to also activate some cellular machinery that acts as a break, possibly limiting its efficacy. This suggests another strategy for fine-tuning gut-hormone drugs: Companies have so far focused on trying to design one drug that binds to multiple hormone receptors, like a master key that can open three different locks. This was a practical choice, Campbell says, because trying to study three separate new drugs in clinical trials would be a logistical “nightmare.” But the optimal combination for weight loss might actually require individual keys that can jigger individual receptors in just the right way—that is, a double or triple combination of drugs.

    It may also eventually be possible to keep increasing the dosage of GLP-1 drugs to push the weight-loss plateau down. Right now, the dose is limited by what people are willing to tolerate. The drugs can cause severe nausea, vomiting, and diarrhea, so they have to be ramped up slowly over many weeks to induce tolerance and minimize side effects. But Novo Nordisk is trialing the drug in Wegovy at up to 16 milligrams a week, more than six times the current maximum dose. Tinkering with other gut-hormone pathways could also help with side effects. GIP receptors, for example, are found in neurons whose activation might suppress nausea, which may in part be why Zepbound seems to have slightly milder side effects.

    Zepbound is likely the first of many leveling-ups from single-action GLP-1 drugs. Even as the science advances, no safe method of losing weight is meant to eliminate the weight-loss plateau—and indeed, you wouldn’t want to keep losing weight indefinitely. But lose more weight? Pharmaceutical companies are betting on a market for that. With obesity drugs projected to become a $100 billion industry by 2030, they are eager for a slice of that massive pie. “The dollar signs are so big now,” Campbell says. Zepbound is the newest weight-loss drug on the block, but it too may eventually be old news.

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    Sarah Zhang

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