MW Some people lose far more weight than others on GLP-1s like Wegovy. Here's why.

By Jaimy Lee

Emerging research shows that some people are 'super-responders' to GLP-1 drugs. Others don't respond at all.

There is emerging research showing that some people are "super-responders" to GLP-1 medications.

Richard Isaacson is a neurologist who works with patients who are trying to prevent Alzheimer's disease. He's also a patient experimenting with his own doctor to see if tiny doses of a GLP-1 medication can improve his health.

Isaacson isn't overweight or obese, but he has seen the research and heard the anecdotes that GLP-1 medications may provide a wide range of health benefits beyond what's included on the labels of the most popular versions of these drugs: Eli Lilly's $(LLY)$ Zepbound and Novo Nordisk's (NVO) (DK:NOVO.B) Wegovy.

Over the two years and four months that he's been "microdosing" Zepbound, Isaacson also discovered that he lost too much weight too quickly, even while taking tiny doses of the medication. He took a total of 11.85 mg of Zepbound last year, whereas most people take a total of 10 mg during just the first month of treatment.

It turns out that Isaacson has a higher-than-normal response to the GLP-1 hormone, which was confirmed by a test developed by scientists at the Institute for Neurodegenerative Diseases of Florida, where he is the director of research.

"Why do I respond to such tiny doses of GLP-1s?" he said. "Because that's my biology."

Isaacson is a so-called super-responder to GLP-1s, and his experience sheds light on how these groundbreaking drugs work differently in different people. GLP-1 super-responders lose the most weight - and are also more likely to struggle with side effects like nausea and vomiting. On the other hand, some people respond very little or not at all to the medications.

GLP-1 use for weight loss has largely been limited to a mix of necessity and access, whether that's having health-insurance coverage or enough disposable income to spend several hundreds of dollars a month on a prescription. But there is now a growing understanding that genetics also play a role in how well these therapies work.

Last month, researchers at the 23andMe Research Institute published a study showing that people with a variant in their GLP-1 receptor lost more weight and experienced more side effects while taking a GLP-1 medication than those who don't have that variant. The research, which is based on a survey of about 28,000 people taking the drugs, also found that they tend to work better in women than in men and in people of European ancestry than in those of Latino and African-American ancestries. There are even differences in how people respond to the different drugs, because Wegovy is a GLP-1 receptor agonist, and Zepbound is a GLP-1/GIP agonist.

"More information is better," said Adam Auton, 23andMe's vice president of human genetics. "As I think about this emerging world, we can help people have a better understanding of what the expectations are and what they might experience."

The fact that these drugs don't work for everyone isn't completely new. Even in the pivotal clinical trials, not all participants ended up with clinically meaningful weight loss, which is considered 5% from baseline. In the Zepbound trial, 15% of patients lost less than 5% of their body weight. In the Wegovy study, that share was 14% of patients. Health insurers often won't reauthorize the medications if someone hasn't lost 5% of their body weight after five or six months.

More research is emerging every day about GLP-1 response. Last week, for the first time, Novo Nordisk shared a subanalysis for a group of people taking a high-dose version of Wegovy who lost 15% or more of their body weight within six months, referring to them as "early responders."

A GLP-1 effectiveness score?

Everyone has GLP-1, which is a hormone that lets you know you're full, but each person has a different "amount" of GLP-1 after they eat. People who have prediabetes, Type 2 diabetes or severe obesity, for example, tend to have lower GLP-1 than those who are metabolically healthy. You can make lifestyle changes to boost your natural GLP-1 like eating more protein, making sure you eat protein and fiber before carbohydrates, eating slowly and doing high-intensity exercise.

"If you exercise rigorously every day, the amount of increase you'll get in GLP-1 is about 30% over ... people who aren't exercising," said Mitch Biermann, an internal medicine and obesity specialist at Scripps Health hospital system in San Diego.

Like many physicians treating patients taking GLP-1 medications, Biermann often fields questions about how well the drugs will work and how long they will need to be taken. For patients who exercise an hour or more every day, he has been able to move them to longer dosing intervals once they hit their goal weight, according to his research. That means those patients can maintain their weight even if they get an injection every two weeks or so rather than every week.

Other obesity specialists, like Tirissa Reid, an endocrinologist at NewYork-Presbyterian and Columbia University, said it can take at least three months to see how well someone is going to respond to treatment. For people planning to take a GLP-1, there are few ways to determine in advance if they'll respond to the pricey medications.

However, some companies and clinics are now selling laboratory-developed panel tests, like the one sold by BlueGenes Lab in Scottsdale, Ariz. (These kinds of tests don't need approval from the Food and Drug Administration and are often part of a "panel" that looks at several genes that can influence GLP-1.) For $249, patients can order the test and mail in a swab, and after a few weeks they receive a GLP-1 "effectiveness score."

"Certain people genetically are going to be predisposed to have a harder road to be successful and probably actually shouldn't take this drug," said BlueGenes Lab CEO Nick Glimcher. "This test really should be evaluated by the consumer to say, 'Hey, is this something that's going to be effective for me before I shell out $300 a month for six months to just find out that it's not effective.'"

23andMe recently added GLP-1R and GIPR to its Total Health platform, which provides insights about an individual's health using their genetic data. It costs $399 for the first year. Auton doesn't think having this information will stop people from taking GLP-1s, but he thinks it can help people talk to their clinicians about taking a more personalized approach to treatment. An individual with a variant on both their GLP-1 and GIP receptors is 14 times more likely to have nausea from Zepbound, according to the 23andMe research. That means they may want to increase the dose more slowly rather than sticking to the standard titration schedule.

"If I was starting a journey of taking one of these medications," Auton said, "it might not change my decision as to whether I'm going to take that medication or not, but it might better prepare me for what the experience might be, right?"

GLP-1s remain the most popular category of medicines in the U.S. right now, making up almost 8% of all prescriptions in the first quarter of this year, according to Truveta Research, which pulled its data from electronic medical records. Millions of Americans have tried the drugs, which have revolutionized the way physicians treat weight loss, but personalizing who gets which drugs is still a long way off - if it ever happens.

"The problem with personalized medicine and precision-based care isn't [that] we don't know how to do it," Isaacson said. "It's that the medical system isn't set up to be able to allow doctors to do it, both from a time and a cost perspective."

-Jaimy Lee

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May 18, 2026 13:30 ET (17:30 GMT)

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