Can amylin weight-loss drugs compete in a world of GLP-1s?

For the past 7 years, pharmaceuticals that work as glucagon-like peptide 1 (GLP-1) receptor agonists have dominated the weight-loss and diabetes markets. These drugs, currently sold by Novo Nordisk and Eli Lilly and Company, have raked in hundreds of billions of dollars in sales. For a while, the GLP-1s were available only as injectables, then this year, pills, too, made it to the market.

But GLP-1s are far from perfect. Their undesirable qualities include side effects such as nausea and muscle loss. And the industry titans know well that being complacent is not the name of the game.

In the quest to bring new generations of weight-loss and diabetes drugs to market, Novo Nordisk, Lilly, and several other companies, big and small, have set their sights on targets other than GLP-1. Among them is amylin, a hormone whose analogs were once seen as promising candidates to become weight-loss and antidiabetic medicines. Those molecules were shelved for many years but are now being dusted off.

The peptides and small molecules under development elicit weight loss by mimicking amylin, a naturally occurring hormone that plays a role in glucose regulation. And while some companies, such as Lilly, are testing their analogs as stand-alone therapies, others, including Novo Nordisk, are combining them with GLP-1s.

Wall Street analysts were particularly excited about amylin candidates for their promise in areas where GLP-1s fall short. Yet as clinical trial results begin to pour in, investor excitement seems to be ebbing. Executives from companies developing the candidates, however, say the data are encouraging and could lead to a class of medicines that are better, with or without GLP-1 companions. Whether these molecules will become game changers is a question not likely to be answered until the first ones hit the market.

Amylin analogs in a GLP-1 world

Semaglutide, the main molecule in Novo Nordisk’s popular Ozempic and Wegovy, acts like the GLP-1 hormone secreted by the intestine. The chemical messenger regulates appetite by slowing the emptying of the stomach. It does that by binding to receptors in the hindbrain, stomach, and pancreas. Tirzepatide, the active ingredient in Lilly’s Mounjaro and Zepbound, works similarly while also acting on another class of receptors known as gastric inhibitory polypeptide (GIP) receptors.

The popularity of these medicines is unprecedented. In 2025, the combined sales of Lilly’s tirzepatide drugs were around $36 billion, outpacing Merck & Co.’s oncology drug Keytruda, which has been the best-selling drug since 2023. A 2025 poll by the nonprofit KFF found that one in eight US adults report being on GLP-1 medications.

But despite their explosive demand, GLP-1s have their share of drawbacks. “GLP-1s are the first in class, but that doesn’t make them the best in class,” says Mike Ward, global head of life sciences and health-care thought leadership at the analytics firm Clarivate, who has spent over 30 years following trends in the life sciences industry.

Some studies show that up to 40% of the weight loss observed in patients on semaglutide is attributable to loss of lean muscle mass, which is viewed as a major shortcoming. Tirzepatide suffers the same problem but to a lesser extent.

Moreover, over 40% of people who start taking GLP-1s quit the medicines within 2 years due to high costs and gastrointestinal side effects such as nausea, diarrhea, vomiting, and constipation, according to a study published in JAMA Network Open last year. Once people stop, the lost weight comes rushing back—faster than after ending behavioral weight-loss programs, according to recent research published in the British Medical Journal. And some people don’t respond to GLP-1 medicines at all.

Enter amylin analogs—molecules that mimic amylin, a peptide co-secreted with insulin by the pancreas. Like GLP-1s, amylin analogs act on brain receptors but have distinct mechanisms of action and functions. Some studies indicate that amylin induces greater satiety than GLP-1s do.

Attempts to develop amylin analogs predate efforts to make GLP-1 receptor agonists, Ward says. Researchers have known the role of amylin in blood-sugar regulation since the late 1980s. Based on that discovery, Amylin Pharmaceuticals began working on making synthetic amylin in 1995. Five years later, it partnered with Lilly to develop pramlintide, an amylin analog for the treatment of diabetes.

The US Food and Drug Administration approved the peptide for the treatment of types 1 and 2 diabetes in 2005. But pramlintide has a short half-life, requiring users to inject it before every meal. Bristol Myers Squibb bought Amylin for $5.3 billion in 2012 and ultimately sold it to AstraZeneca, which deprioritized any new work on amylin analogs.

Dimitris Papamargaritis, an associate professor in diabetes and endocrinology at the University of Leicester, says animal studies suggest that amylin analogs can spare muscle, which is why several companies have decided to look at amylin with a fresh set of eyes.

Data on new-generation amylin analogs

Among the companies developing amylin analogs, Novo Nordisk, the pioneer of GLP-1s, is furthest along.

Novo Nordisk anticipates a decline in sales and profits from its GLP-1 drugs this year due to rising competition from Lilly. Still, the company was hoping that 2026 would bring good news: the publication of clinical trial results for CagriSema, a half-and-half combination of semaglutide and a new peptide called cagrilintide, a long-acting amylin analog.

In its initial studies, Novo Nordisk found that cagrilintide led to more weight loss and better muscle preservation than semaglutide. Combining the two molecules yielded better results than either molecule alone, though the side effects from the combo were higher.

But for its next study, Novo Nordisk decided on a bold move. In a Phase 3 head-to-head trial, the company compared CagriSema’s performance with that of Lilly’s tirzepatide, which is known to achieve greater weight loss than semaglutide. And with those results, published in February, Novo Nordisk may have fouled its own nest.

The findings showed that 2.4 mg each of semaglutide and cagrilintide resulted in a 23% reduction in body weight, whereas 15 mg of tirzepatide resulted in a 25.5% reduction.

Andy Hsieh, a biotech analyst at the investment bank William Blair, says his initial reaction upon seeing Novo Nordisk’s findings was, “Oh man! . . . Novo spent so much time and money on this trial just to prove that a competitor is better. A Lilly sales rep could go to the doctor and say, ‘Look, our competitor is saying that our drug is better.’”

Still, the silver lining for Novo Nordisk is that it has shown that an amylin drug can lead to weight loss, Hsieh says. Novo Nordisk has already asked the FDA for approval to sell once-weekly CagriSema injections.

Lilly, too, has an amylin analog, eloralintide, in its portfolio. And, as with tirzepatide, it seems to be the one to beat. In a Phase 2 trial last year, a 9 mg dose of eloralintide achieved up to 20% weight reduction compared with a placebo. The company is now testing the molecule in Phase 3 studies. Separately, Lilly is also investigating the candidate in combination with tirzepatide.

Roche isn’t far behind. In 2025, the firm paid $1.5 billion to enter a partnership with Zealand Pharma to codevelop Zealand’s amylin analog, petrelintide. The two companies are studying the molecule as a monotherapy and in combination with Roche’s own GLP-1 and GIP candidate.

In March, Roche and Zealand released Phase 2 clinical trial data for a once-weekly injection of petrelintide showing nearly 10% weight reduction among participants with minimal side effects. But the results did not match analysts’ expectations, and Zealand’s shares tumbled in their wake. In a note to investors, analysts at the investment bank Jefferies Financial Group say that although petrelintide demonstrated good tolerability, meaning no side effects such as vomiting and nausea, the amount of weight loss did not match that of Lilly’s amylin molecule.

AbbVie, which paid $350 million to license a long-acting amylin analog from the firm Gubra, also recently announced Phase 1 data. The trial delivered weight loss of less than 10%, far less than the amount Lilly reported.

Quality versus quantity in weight loss

Much of the recent clinical trial data may have underwhelmed investors, but executives at companies developing drugs targeting amylin receptors are optimistic. They say the narrative around weight loss needs shifting from quantity to quality.

Raj Kannan, CEO of Alveus Therapeutics, which raised $160 million in series A financing in January, says the next generation of drugs is going to be all about the quality and durability of weight loss—and that is where amylin analogs hold promise. The biotech firm has two such analogs, a peptide and a small molecule, in preclinical development. “The unmet needs in the marketplace are having better-tolerated drugs and sparing the muscle loss,” Kannan says. “Drugs that will address those are going to be the clear winners in the next 4 to 5 years.”

For years, GLP-1 medicines have come as weekly injectables. Then this year, weight-loss pills hit the market. First came Novo Nordisk’s Wegovy pill and then Lilly’s recently approved small-molecule pill Foundayo. Both are taken daily, but the more frequent the dosing, the more patients may have to deal with gastrointestinal side effects, says Jacob Jeppesen, Alveus’s chief scientific officer. Alveus’s amylin injectable is designed for weekly dosing.

And although CagriSema didn’t match tirzepatide in the latest study, Jeppesen says he thought the weight loss it offered was impressive and of better quality than that of GLP-1s. He also says people are too focused on the kilograms lost. “I think we should move away from that and look at the overall metabolic health. That is where our company is coming from,” he says.

Utpal Singh, Zealand’s chief scientific officer, concurs. “The weight loss that you can’t keep isn’t the weight loss you have achieved,” he says, adding that amylin analogs offer a significantly better experience, with fewer side effects compared with GLP-1s. In a presentation (PDF) to investors, Zealand notes that nearly 70% of clinical trial participants on the highest dose reported no gastrointestinal adverse events at any time.

“You see a profound difference in tolerability of GLP-1s and amylin analogs, and that is where amylin drugs will set the benchmark,” Singh says.

Winner in weight-loss-drug contest takes it all?

The global market for weight-loss drugs is expected to reach $150 billion by 2035, according to research by Morgan Stanley, an increase from a previous forecast of $105 billion. So it’s not surprising that firms are also researching approaches beyond GLP-1s and amylins.

Arrowhead Pharmaceuticals, for example, is developing RNA-based therapies that silence specific genes expressed in the liver and adipocytes. “GLP-1s are great, but it looks like people can’t stay on them forever,” says James Hamilton, Arrowhead’s chief medical officer. “What we are developing could be used as something like maintenance therapy where you could get subcutaneous injections every 3 to 6 months.”

The market opportunity also resulted in a dramatic legal battle between Pfizer and Novo Nordisk last year, when the two companies fought over buying Metsera, a start-up developing weight-loss drugs. In September, Pfizer offered to buy Metsera for $4.9 billion, but less than a month later, Novo Nordisk made an unsolicited bid of $6.0 billion in cash. Pfizer called Novo Nordisk’s move “reckless and unprecedented” and emerged as the eventual winner in the Metsera tug-of-war.

Ward from Clarivate says Pfizer’s acquisition of Metsera was its way of getting back into the game after the failure of its in-house GLP-1 molecule last year. One of Metsera’s drug candidates is an amylin analog for weight loss, he notes.

According to Ward, predicting which companies will emerge as champions and which ones will wash out is hard. But to him, it seems that dethroning Lilly, the first-ever pharmaceutical company to reach a market value of $1 trillion, will prove challenging. “I think Lilly clearly has the firepower,” he says. “It is going to take a lot for someone to wrestle that away from them, at least in the near future.”

And as for amylin analogs, Papamargaritis, the Leicester researcher, says that, based on current data, Lilly’s molecule is leading in terms of the amount of weight loss it can offer, but that doesn’t mean the market doesn’t have a place for other amylin analogs as well as drugs that target other receptors, such as glucagon.

“Right now, the only options on the market are semaglutide and tirzepatide,” Papamargaritis says. “Having new molecules will give doctors more options to select a drug that caters precisely to individual patients’ needs.”

CORRECTION

This story was updated on April 10, 2026, to correctly describe the intended dosing of the injectable amylin-mimicking weight-loss drug being developed by Alveus Therapeutics. It is weekly, not monthly to quarterly, dosing. In addition, text incorrectly suggesting that amylin analogs hold the promise of infrequent administration was removed. 

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