Christina Szalinski

For people with obesity or type 2 diabetes, glucagon-like peptide 1 (GLP-1) agonists (including Mounjaro, Wegovy, and Ozempic) have been labeled miracle drugs. But they aren’t miraculous for everyone. Research indicates a significant portion of people discontinue using them within a year.

The main problems with GLP-1 agonists are that they are expensive and have a fairly high rate of side effects — such as nausea, vomiting, diarrhea, or constipation. Another big one is muscle loss.

A new study, published in Nature, shows a potential alternative to GLP-1 agonists with fewer side effects, at least in mice and nonhuman primates.

This lack of side effects, particularly in how the potential drug causes no muscle loss — and in fact engages muscle for some of its effect — sets it apart and makes it a potential alternative to GLP-1s. The key is not just reducing appetite but also increasing energy expenditure.

How It Works

The new approach targets a protein called NK2R — a member of the neurokinin receptor family, which has a role in a variety of physiological processes, including pain sensation, anxiety, and inflammation. 

“We were looking to see genetic linkages to metabolic health, and there NK2R was,” said Zach Gerhart-Hines, PhD, a professor studying molecular metabolism at the University of Copenhagen in Denmark and principal investigator of the study. The group then created a few long-acting agonists that are selective for NK2R. So far, they’ve tested them in mice and nonhuman primates.

“The data on new medicines targeting NK2R is very promising and highlights the potential of both reducing food intake and increasing energy expenditure,” said Daniel Drucker, MD, an endocrinologist and researcher at Lunenfeld-Tanenbaum Research Institute in Toronto who was not involved in the study.

“The drug activates a certain region in the hindbrain of the animal, which is controlling food intake, and it does so by reducing appetite without increasing nausea or vomiting,” explained Frederike Sass, a research assistant at the University of Copenhagen in Copenhagen, Denmark, who led the study.

Gerhart-Hines said that even at the highest dose, there were no incidents of vomiting among the nonhuman primates. Mice can’t vomit, but there are ways to tell if they feel unwell from a drug. One way researchers test that is to start feeding the mice sweetened water at the same time they’re given a drug. Then later, when the mice are no longer on the drug, they’re given a choice between sweetened and unsweetened water. If they weren’t feeling well on the drug, they’ll choose plain water because they associate the sweet water with feeling bad, otherwise mice prefer sweet water. Sass said that with the NK2R agonist, they continued to drink sweet water after the treatment, whereas when they gave the mice semaglutide, the mice preferred plain water posttreatment.

The researchers also monitored the animals’ psychological health, as NK2R has been associated with anxiety, but they observed no behavioral changes.

The Key Mechanism at Work

One big question is how the NK2R agonists work. The amphetamines people used for weight loss during the 1950s and 1960s worked by making people more active. GLP-1 agonists reduce appetite and lower blood sugar. This is not that. In their studies with animals, the researchers didn’t observe that the animals were more active nor were there changes in other biomarkers like insulin. So far, the main difference they found with the NK2R agonists is an increase in thermogenesis in certain muscles.

Another benefit of the NK2R treatments is that they don’t seem to have a big impact on lean mass — the nonfat component of body weight, namely muscle, bones, and organs. Studies indicate that 25%-39% of weight loss on GLP-1 agonists is lost muscle. According to DEXA scans of the mice, Gerhart-Hines said they observed no lean mass loss. (In mice, he noted, GLP-1 agonists can cause up to 50% lean mass loss).

And for people with both diabetes and obesity, “what we found with NK2R is that obese and diabetic models, whether mice or monkeys, respond much better to that treatment in terms of glucose control and body weight loss,” Gerhart-Hines said. He explained that GLP-1 agonists don’t work quite as well for weight loss in people with diabetes because the drug stimulates insulin production in a system that already has insulin issues and can cause more sugar to be stored as fat.

Further, GLP-1 agonists are peptide drugs, which are expensive to make. The NK2R agonists are small molecules that would be cheaper to produce, Gerhart-Hines believes. One candidate they’re testing would likely be given once daily, another once weekly.

The current surge in obesity and diabetes may be a direct consequence of our bodies’ decreased energy expenditure. “Compared to 80s and 90s, the average person is more physically active, but the overarching basal resting energy expenditure has gone down,” said Gerhart-Hines, according to research by John Speakman at the University of Aberdeen, Aberdeen, Scotland. We don’t know why, though, he said, but guesses it could be our diets or climate controlled environments.

But the NK2R agonists are among the many currently being studied for weight loss, and it may be hard to compete with the GLP-1 agonists. “As GLP-1 medicines will soon achieve 25% weight loss and have an extensively studied safety profile, the task of producing better drugs that work well in most people, are well tolerated and also reduce the complications of cardiometabolic disease, is challenging but not impossible,” said Drucker.

Gerhart-Hines said they plan to start trials in humans in the next year, but he suspects it will be another 6 or 7 years before it comes to market, if the trials are successful.

“There’s people who want [a GLP-1 agonist] and can’t even get it,” Gerhart-Hines said. As far as weight loss drugs, he noted, “we are not even saturating the market right now.”