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The newest and much-hyped obesity drugs are, at their core, powerful appetite suppressants. When you eat fewer calories than you burn, the body starts scavenging itself, breaking down fat, of course, but also muscle. About a quarter to a third of the weight shed is lean body mass, and most of that is muscle.
Muscle loss is not inherently bad. As people lose fat, they need less muscle to support the weight of their body. And the muscle that goes first tends to be low quality and streaked with fat. Doctors grow concerned when people start to feel weak in everyday life—while picking up the grandkids, for example, or shoveling the driveway. Taken further, the progressive loss of muscle can make patients, especially elderly ones who already have less muscle to spare, frail and vulnerable to falls. People trying to slim down from an already healthy weight, who have less fat to spare, may also be prone to losing muscle. “You have to pull calories from somewhere,” says Robert Kushner, an obesity-medicine doctor at Northwestern University, who was also an investigator in a key trial for one of these drugs.
Kushner worries about patients who start with low muscle mass and go on to become super responders to the drugs, losing significantly more than the average 15 to 20 percent of their body weight. The more these patients lose, the more likely their body is breaking down muscle. “I watch them very carefully,” he told me. The impacts of losing muscle may go beyond losing just strength. Muscle cells are major consumers of energy; they influence insulin sensitivity and absorb some 80 percent of the glucose flooding into blood after a meal. Extreme loss might alter these metabolic functions of muscle too.
Exactly how all of this will affect people on Wegovy and Zepbound, which are still relatively novel obesity drugs, is too early to say. (You may have heard these same two drugs referred to as Ozempic and Mounjaro, respectively, which are their names when sold for diabetes.) These drugs cause a proportion of muscle loss higher than diet and exercise alone, though roughly on par with bariatric surgery. Lifestyle changes can blunt the loss, but pharmaceutical companies are on the hunt for new drug combinations that could build muscle while burning fat.
The arrival of powerful weight-loss drugs has moved the field beyond simple weight loss, Melanie Haines, an endocrinologist at Massachusetts General Hospital, told me. That challenge is largely solved. Instead of fixating on the number of pounds lost, researchers, doctors, and ultimately patients can focus on where those pounds are coming from.
Doctors currently offer two pieces of standard and unsurprising advice to protect people taking obesity drugs against muscle loss: Eat a high-protein diet, and do resistance training. These recommendations are perfectly logical, but their effectiveness against these drugs specifically is unclear, John Jakicic, a professor of physical activity and weight management at the University of Kansas Medical Center, told me. He is now surveying patients to understand their real-world behavior on these drugs.
Fatigue, for example, is a common side effect. “When you’re tired, and you’re fatigued, do you really feel like exercising?” he said. Haines wonders the same about eating enough protein. The drugs are so good at suppressing appetite, she said, that some people might not be able to stomach enough food to get adequate protein. (Food companies have started pitching high-protein snacks and shakes to people on obesity drugs.)
If patients stop taking Wegovy and Zepbound—and about half of patients do stop within a year, at least in real-world studies of people taking this class of drugs for diabetes—the weight regained comes back as fat more than muscle, says Tom Yates, a physical-activity professor at the University of Leicester. Muscle mass tends not to entirely recover. It’s “almost as if you’re better off staying where you are than going through cycles of weight loss,” he told me.
Yet, he pointed out, the U.K. recommends Wegovy for a maximum of two years. In the U.S., patients who can’t afford the steep out-of-pocket price have been forced to stop when insurance companies abruptly cut off coverage or a manufacturer’s discount coupon expires. These policies are likely to trigger cycles of weight loss and gain that lead, ultimately, to net muscle loss.
Meanwhile, drug companies are already thinking about the next generation of weight-loss therapies. “Wouldn’t it be great to have another mechanism that’s moving away from just appetite regulation?” Haines said. Companies are testing ways to preserve—perhaps even enhance—muscle during weight loss by combining Wegovy or Zepbound with a second muscle-boosting drug. Such a combination could, in theory, allow patients to lose fat and gain muscle at the same time.
Years ago, scientists first became interested in potential muscle-enhancing drugs that mimic mutations found in certain breeds of almost comically ripped dogs and cattle. At the time, they hoped to treat muscle-wasting diseases. The drugs never quite worked for that purpose, but the trial for one such drug, an antibody called bimagrumab, found that patients also lost fat in addition to gaining lean mass. A start-up acquired the drug and began testing it for weight loss in combination with semaglutide, the active ingredient in Wegovy, or Ozempic. And last year, Eli Lilly, the maker of Zepbound, snapped up that company for up to $1.9 billion—in hopes of making its own combination therapy.
Pairing bimagrumab with an existing obesity drug could potentially maximize the weight loss from both. Losing weight tends to get harder over time; as you lose muscle, your body burns fewer calories. A drug that minimizes that muscle loss—or even flips it into muscle gain—could help patients boost the amount of energy their body expends, while Wegovy or Zepbound suppresses calories consumed. The mechanisms of how this might actually work in the body still need to be understood, though. Previous studies of bimagrumab found that patients grew more muscle, but they didn’t necessarily become faster or stronger. Haines, who is planning a small study of her own with bimagrumab, is most interested in how the combination affects not the structural but the metabolic functions of muscle.
Bimagrumab is the furthest along of several drugs that tinker with the same pathway for muscle growth. The biotech company Regeneron recently published promising data on two of its muscle-enhancing antibodies paired with semaglutide in primates; a trial in humans is due to begin later this year. The start-up Scholar Rock is testing another antibody called apitegromab. Other companies are interested in combining the obesity drugs with different potential muscle boosters that work by mimicking certain hormones such as apelin or testosterone. If they succeed, the next generation of drugs could help sculpt a more muscular body, not just a smaller one. Eating less can only do so much to better your health.
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Sarah Zhang
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