Danielle Rosas had tried all the usual avenues to lose weight—modifying her diet, increasing her exercise—but the weight always came back. In 2020, she turned to Ozempic. She was 225 pounds at the time. “My weight has fluctuated a lot throughout my adulthood,” says Rosas, now 36.

After three months of injecting the drug once a week, she’d lost about 5 percent of her body weight, around 15 pounds. She was disappointed. She had hoped to lose more—in trials, patients had lost three times as much, although over a much longer period. What’s worse, she felt nauseous and generally unwell a lot of the time. She thought the side effects weren’t worth the little weight she had lost, so she decided to go off the drug.

The Age of Ozempic is a WIRED special series exploring a transformative generation of weight-loss drugs. Read the rest here.

Rosas’ case illustrates the reality of new anti-obesity drugs: They don’t work equally well for everyone. Semaglutide, which goes by the brand names Ozempic and Wegovy, has shown around 15 percent weight loss in clinical trials, while tirzepatide—sold as Mounjaro and Zepbound—has achieved around 20 percent. But those are averages, and in the real world, drugs don’t always perform as well as they do in carefully controlled trials.

“Everyone expects these medications to be magic,” says Hans Schmidt, director of the Center for Weight Loss & Metabolic Health and chief of bariatric surgery at Hackensack University Medical Center in New Jersey. In fact, people have a wide range of responses to anti-obesity medicines.

While many people do remarkably well on them, a subset lose little to no weight on new GLP-1 drugs—so-called because they mimic a naturally occurring hormone in the body called GLP-1 that’s involved in regulating blood sugar, appetite, and digestion. In a trial of semaglutide, about a third of people lost less than 10 percent of their weight; in a study for tirzepatide 16 percent of people on the highest dose lost less than 10 percent of their weight. In the same trials, about 14 percent of participants on semaglutide lost less than 5 percent of body weight; for those on the highest dose of tirzepatide, that figure was 9 percent.

That tracks with what Schmidt is seeing at his practice. He says around 15 percent of his patients don’t respond well to GLP-1s. Of course, part of it comes down to whether patients are able to stay on the medications and remember to take them every week. Some people, like Rosas, aren’t able to tolerate the side effects. “If be on the medication,” Schmidt says.

But among those who do stick it out, some individuals still don’t shed the pounds. “I’m on week 10, zero weight loss,” said one woman on Tiktok in reply to a video on so-called nonresponders. “I’ve been on it for almost a year and have only lost 10 lbs,” said another. “I’ve been on the shots since Jan. Now on the highest dose and have lost nothing,” read another comment.

It’s not clear why some people on these drugs lose a lot of weight while others don’t lose any. “We still don’t understand most of the variation in response,” says Ewan Pearson, professor of diabetic medicine at the University of Dundee in Scotland. There are a few known predictors of how patients will fare, though. For instance, women tend to lose more weight than men on GLP-1 drugs, possibly because they have a different fat distribution compared to men, or because their smaller average size could mean higher exposure to the drug.

And while GLP-1 drugs were first approved as a diabetes treatment to improve blood sugar levels, they’re less likely to produce significant weight loss in people with type 2 diabetes. Researchers have suggested genetics, altered microbiomes, and other medications that promote weight gain as possible reasons for this. “A lot depends on a person’s physiology and biology. We can’t expect that a drug will be a one-size-fits-all for everyone,” says Amy Rothberg, an endocrinologist at the University of Michigan.

GLP-1 drugs lead to weight loss by slowing the movement of food in the stomach and by interacting with receptors in the brain to promote a feeling of fullness. Some people taking them report less “food noise”—they no longer have cravings or think about food all the time. As a result, they eat less. Patients start on a low dose that’s gradually increased each week. Schmidt says some people may not respond to the lower doses but do eventually see weight loss as the medication is ramped up.

Without lifestyle changes, these medications are likely to be less effective for weight loss. Novo Nordisk, which makes Ozempic and Wegovy, and Eli Lilly, which makes Mounjaro and Zepbound, stress that the drugs are meant to be used alongside a healthy diet and exercise. In trials of semaglutide and tirzepatide, the medications were paired with a reduced-calorie diet and increased physical activity. Clinical trials are often the best-case scenario when it comes to a drug’s efficacy because they involve careful tracking of participants and many follow-up visits with providers. In real life, patients may not follow their weight-loss plan as diligently or see their doctor as regularly.

And while these drugs help curb appetite, they don’t magically eliminate all temptations. After all, there is a major social component to eating food. “We may eat because it looks good, tastes good, we’re in the company of others, or because it’s available,” Rothberg says. A person who has those environmental pushes or stimuli competing with the drug won’t lose as much weight as the person who doesn’t have to deal with those factors, she argues.

Differences in metabolism, or how people break down food and convert it into energy, could also be at play. A person’s age and hormone function, as well as the amount of physical activity they get, can have an effect on metabolism.

Researchers are also looking into whether genetic factors may explain some of the variability in response. In 2022, Pearson and his colleagues published a paper that identified a gene called ARRB1 that seems to be involved in glucose control. When they looked at genetic data from more than 4,500 adults, they found that people with certain variants in this gene have lower blood sugar levels while taking GLP-1 drugs.

The ARRB1 gene is involved in recycling the GLP-1 receptor within the cell and returning it to the cell’s surface. It’s likely, Pearson says, that people with these variants—about 2 to 3 percent of the white population and 11 percent of Hispanics—have more of these receptors on their insulin-making pancreatic cells. Because GLP-1 drugs work by binding to these receptors, the bigger reduction in blood sugar may be explained by greater binding activity spurring more insulin production.

But in Pearson’s study, the genetic alterations weren’t connected with weight loss, meaning the effect was probably limited to the pancreas. Even so, it means that there are likely to be genetic factors that account for some of the weight loss response. And it may be that variants in multiple genes, rather than just one, drive people’s different responses. Pearson’s group is now working with researchers at the University of Montreal to study genetic factors and weight loss in people on GLP-1 drugs.

For some GLP-1 nonresponders, it could be that another mechanism is involved in their obesity, says Rehka Kumar, an endocrinologist and chief medical officer of Found, a company that provides personalized weight loss plans. “It’s possible that whatever drove them to gain weight isn’t necessarily related to the GLP-1 pathway,” she says. “They may do better on a medicine that works differently.”

Researchers at the Mayo Clinic are trying to categorize people based on their obesity “phenotype,” or the behavioral components behind the disease. Mayo gastroenterologist Andres Acosta and his colleagues have used machine-learning methods to describe four major types of obesity: “hungry brain,” in which people never feel full; “hungry gut,” where people eat until they are full but feel hungry again soon after; “emotional hungry,” which are people who eat to cope with emotional issues or to reward themselves, regardless of whether they’re hungry; and “slow burn,” people who don’t burn calories fast enough. Research by Acosta has shown that people with the hungry-gut type lose more weight on GLP-1 drugs than the other types.

Nonresponders may not have to wait long for other options. GLP-1 drugs only seem to be getting more effective. Whereas semaglutide targets just the GLP-1 receptor, the newer tirzepatide targets GLP-1 plus another receptor, GIP. Drugmakers are studying whether new drugs that target more than one receptor involved in obesity could boost weight loss. “As we get more sophisticated with these gut hormone combinations, I think we’ll be able to see more responsiveness in the population,” Kumar says.

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