Some people don’t lose weight with GLP-1s. Evidence is building that the drugs are helping anyway

By Meg Tirrell, CNN

(CNN) — For the majority of people who start using GLP-1 medicines with the hope of losing weight, the drugs can feel almost miraculous: Cravings are quieted. Exercise can become easier and more fun. Pounds that stubbornly remained for years finally dissipate.

But for a smaller subset of people, the medicines don’t help with weight loss. Clinical trials suggest that about 10% to 15% of people who try GLP-1s, such as Wegovy and Zepbound, are “non-responders” when it comes to substantial weight loss. A study published last week suggested that genetics may play a role.

But research, including new findings published Tuesday, is also continuing to paint a picture of GLP-1 medicines’ benefits independent of weight loss. Clinical trials in heart health, for example, have suggested that the medicines can reduce the risk of heart attacks and strokes, and improve outcomes in heart failure, even when participants don’t lose weight – or, in some cases, possibly even if participants gain weight.

The latest findings shed light on how the drugs may improve liver health. Wegovy, made by Novo Nordisk and based on the active ingredient semaglutide, was approved by the US Food and Drug Administration in August for a serious liver disease called metabolic dysfunction-associated steatohepatitis, or MASH, estimated to affect about 6% of US adults. The drug was shown in a clinical trial to help dramatically improve markers of the disease.

“For the most part, I think the dogma is that this improvement is driven by weight loss,” said Dr. Daniel Drucker, a pioneer of GLP-1 research at the University of Toronto whose lab produced the new study. “But we have seen hints in our lab that weight loss isn’t the whole story.”

Drucker argues that the mounting evidence should change the way health insurers and government programs consider whether to pay for the medicines: Instead of assessing weight loss as a measure of their success, they should take into account their other benefits “across a wide range of very serious diseases.”

“Insurance companies have historically required at least 5% weight loss after three to four months of treatment in order to continue covering GLP-1 treatment,” said Dr. Jody Dushay, who prescribes the medicines in her practice at Beth Israel Deaconess Medical Center in Boston. “With new information about metabolic benefits separate from weight loss, this will definitely need to be reconsidered.”

She estimates that about 5% to 8% of patients in her practice are what she calls “weight non-responders” to GLP-1s. The drugs are so named for the hormone they mimic, which plays a role in insulin secretion, stomach emptying and appetite.

“But with the increasing number of indications for these medications,” Dushay told CNN in an email, “we are going to see (or, we need to look for!) benefits in people who do not meet weight loss ‘responder’ criteria.”

‘Elegant work’

Drucker’s study, led by postdoctoral fellow Dr. Maria Gonzalez-Rellan, sought to understand why semaglutide appeared to improve markers of MASH regardless of whether participants lost weight in clinical trials.

The research team did this, in part, by creating essentially “weight non-responders” out of lab mice, eliminating GLP-1 receptors in the brain in a group of them to make it so they don’t lose weight with GLP-1 medicines, Drucker said.

“That allows us to then say, ‘OK, if we prevent weight loss, because that’s mediated by the brain, do we still see the benefits of GLP-1 and improving liver health?’ ” he explained. “And the answer is: Absolutely, we see substantial benefits, even in the absence of weight loss.”

The team identified a group of cells in the liver that, when stimulated by GLP-1, kick-start a process that communicates with the immune system to “quiet down inflammation,” Drucker said. “It’s this very rare population of blood vessel cells that’s driving the reduction of inflammation.”

To further validate their findings, the group studied what happened when mice engineered to lack GLP-1 receptors in those liver cells lost a substantial amount of weight: no liver improvement.

“It’s elegant work,” said Dr. Harlan Krumholz, a cardiologist and professor at Yale School of Medicine who wasn’t involved in the study.

He pointed out, though, that since the study was done in mice, it can’t be said with certainty that the same mechanisms are at play in people.

“But we can now say that this is a biologically plausible explanation for why some benefits of these drugs appear to extend beyond simple weight reduction,” Krumholz added.

GLP-1s’ effect on inflammation

The ability of GLP-1 medicines to tamp down inflammation may be a key reason they help with heart conditions and kidney disease in ways independent of weight loss, as well.

A study of results from a major cardiovascular outcomes trial of Wegovy in 2024 found that its ability to reduce the risk of people having a second heart attack or stroke wasn’t dependent on how much weight people lost.

The study author, Professor John Deanfield from University College London, suggested that “positive impacts on blood sugar, blood pressure, or inflammation, as well as direct effects on the heart muscle and blood vessels,” may be at play.

That’s not to say weight loss doesn’t also help – and is probably a key driver of improvement in conditions including arthritis and sleep apnea, said Drucker, who has received consulting and speaking fees from companies that make GLP-1 medicines.

But the new findings add to the body of evidence suggesting that the medicines could be used in more tailored ways, taking into account their sometimes substantial costs and side effects, which can include nausea and other gastrointestinal symptoms.

“It’s very important to understand: Should we be trying to maximize the weight loss, and sometimes that means using the highest doses of the medicine, and sometimes that means more side effects?” Drucker said. “Or, in this case with metabolic liver disease, we could only use a smaller dose of the medicine and not have so much of the adverse events, and it wouldn’t cost the patient as much money because they’re not taking as much of the drug.

“So,” Drucker added, “it’s really clinically relevant to understand how these medicines work in every one of these conditions.”

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