Since Ozempic blasted onto the stage in 2017 with its approval for type 2 diabetes, drugmakers Novo Nordisk and Eli Lilly have been battling to leapfrog each other with newer and more effective medicines to turbo-charge diabetes and weight-loss results with the class known as GLP-1 receptor agonists.
Novo Nordisk’s latest attempt in weight loss, a combination drug called CagriSema, matched the bar set by Lilly’s currently approved medicine, Zepbound, but didn’t cleanly surpass it in late-stage clinical trial findings reported Friday.
The experimental drug puts semaglutide, the ingredient in Ozempic and the weight-loss drug Wegovy, together with a medicine called cagrilintide to make the combination Novo Nordisk calls CagriSema.
The 68-week study showed participants on CagriSema lost about 23% of their body weight, compared with 12% for those taking cagrilintide by itself, 16% for those on semaglutide, and 2.3% for people on a placebo.
That means the study met its main goal, but those watching the weight-loss drug race closely had pegged their hopes on an average result for CagriSema of at least 25% weight loss, which would set a new bar for a field that’s already been revolutionized by GLP-1 drugs.
Lilly’s Zepbound, approved in November 2023 as the Indiana-based drug giant’s answer to Novo Nordisk’s Wegovy, showed 21% average weight loss after 72 weeks for its highest dose in its Phase 3 trial, and a mid-stage study of another Lilly experimental medicine, called retatrutide, showed 24% weight loss after just 48 weeks.
“We are encouraged by the weight loss profile of CagriSema demonstrating superiority over both semaglutide and cagrilintide in monotherapy,” Martin Holst Lange, executive vice president for development at Novo Nordisk, said in a company news release Friday. He said Novo Nordisk would use insights from the trial “to further explore the additional weight loss potential of CagriSema.”
Novo Nordisk’s stock fell about 19% in early Friday trading on the news, wiping out tens of billions of dollars from the Danish drug giant’s market value.
CagriSema’s side effects appeared to be similar to other drugs in the GLP-1 class; the company said the most common ones were gastrointestinal, with the “vast majority” mild to moderate and going away over time. Only just more than half of participants got up to the highest dose of the drug, though, leading some to question if the combination may not be as tolerable at high doses.
Novo Nordisk said it expects results from a second Phase 3 trial of the medicine, this one in people with type 2 diabetes, in the first half of 2025.
The study reported Friday, which Novo Nordisk calls REDEFINE 1, enrolled people with obesity or who are overweight and have at least one health condition – the same group for whom Wegovy and Zepbound are approved for weight loss. Participants’ average body weight to start was 106.9 kilograms, or about 236 pounds.
A medical ‘arms race’
Novo Nordisk’s Ozempic and Wegovy are based on the active ingredient semaglutide, which mimics a hormone known as GLP-1 that’s important for insulin secretion, digestion and appetite. Wegovy was approved by the FDA in 2021, after showing it helped people lose about 15% of their body weight, on average, in a 68-week clinical trial.
Lilly answered with Mounjaro and Zepbound, approved in 2022 and 2023 for diabetes and weight loss, respectively. They use the active ingredient tirzepatide, which mimics not just GLP-1 but another hormone called GIP, to soup up results.
A Lilly-sponsored head-to-head trial earlier in December reinforced findings from separate studies that Zepbound yielded greater weight loss over 72 weeks, on average, than Wegovy — 20% compared with about 14%.
The competition has also been a benefit to the drugmakers and their investors; Lilly’s market value now surpasses $700 billion, quintupling over the last five years as GLP-1 drugs rake in billions of dollars in annual revenue. Novo Nordisk’s stock tripled in that period, to more than $300 billion.
Practitioners point out the field is moving at an incredible pace.
A previous crop of weight-loss drugs, like Qsymia, a combination of older medicines not part of the GLP-1 class, and liraglutide, an earlier GLP-1 medicine sold under the brand name Saxenda, produced maximum weight loss of 8 to 11%, on average, said Yale School of Medicine’s Dr. Jorge Moreno.
Weight loss of 25%, Moreno and Grunvald noted, would reach results obtained by bariatric surgery. And in Novo Nordisk’s CagriSema trial, 40% of participants did lose at least 25% of their body weight – just not enough to bump the trial’s overall average result past that benchmark.
“Five years ago, if you’d said, ‘Novo Nordisk is going to have a new drug [where] 40% of people will get 25% weight loss, but that’ll be pretty disappointing in 2024,’ we would have said, ‘You’re smoking something, right?’” said Dr. Daniel Drucker, a pioneer of research into GLP-1 at the University of Toronto, who’s worked with companies developing these medicines.
Even if next-generation medicines show greater degrees of weight loss, Drucker said, it takes several years for trials to prove benefits on other outcomes like those, which may be more meaningful to patients and doctors.
Competition through combination
With CagriSema, Novo Nordisk is targeting an additional hormone called amylin, in addition to GLP-1. Lilly’s retatrutide builds on tirzepatide’s GLP-1 and GIP by adding yet another hormone target, glucagon – giving it the moniker “Triple G.”
Another drug company, Amgen, has taken yet another approach, blocking GIP instead of activating it, as tirzepatide does; its drug, dubbed MariTide, produced about 20% weight loss, on average, over the course of a year in mid-stage trial results reported in November.
The medicine is designed to be administered less frequently than Wegovy and Zepbound – with injections once a month or less, compared with current drugs’ weekly shots. Still, the results led investors to sell Amgen’s stock over fears it wouldn’t be able to catch up with competitors.
“It just shows you how fast the field is moving and how high the expectations are moving,” said Drucker.
The signal that targeting amylin could preserve lean mass during weight loss — a key question about GLP-1 drugs — has so far been from animal studies, Drucker pointed out, leading him to question whether that result would bear out in human studies.
But he noted yet another hormone, glucagon, which is the third addition to Lilly’s retatrutide, “is very good at getting fat out of the liver,” so it may be especially helpful for people with metabolic liver disease.
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“The next very important chapter of the story, once we get beyond the weight loss, will be to say, ‘OK, what’s the unique character of each one of these partners, and does this bring a unique benefit?’” Drucker said.
But it’s also crucial to know if they affect safety, he said.
“GLP-1 drugs alone have a very powerful track record of safety,” Drucker said, “but every time we add something to it, we’re starting again.”
And even just targeting one hormone, GLP-1, has been transformative.
“For years, we always thought it was just willpower, like somebody was overweight because they just couldn’t stop eating,” said Dr. Clayton Runfalo, who practices family medicine at Ochsner Health in Louisiana.
A better understanding of these hormones over the last few decades have changed that, Runfalo said. Now he sees GLP-1 drugs as tools, along with behavior change, that have been “really, really good for us as far as helping people get healthier.”