Dozens of new obesity drugs are coming: these are the ones to watch

Next-generation obesity drugs will work differently from Ozempic and Wegovy — aiming to deliver greater weight loss with fewer side effects

For Kristian Cook, every pizza box he opened was another door closed on the path to overcoming obesity. “I had massive cravings for pizza,” he says. “That was my biggest downfall.”

At 114 kilograms and juggling a daily regimen of medications for high cholesterol, hypertension and gout, the New Zealander resolved to take action. In late 2022, at the age of 46, Cook joined a clinical trial that set out to test a combination of the weight-loss drug semaglutide — better known by its brand names, Ozempic or Wegovy — and an experimental drug designed to preserve muscle while shedding fat.

Muscle loss is a big concern for people on anti-obesity medications such as semaglutide. These ‘GLP-1 agonists’ mimic a natural gut hormone — glucagon-like peptide 1 — to suppress appetite and regulate metabolism. But reducing calories leads to an energy deficit, which the body often makes up for by burning muscle. The experimental drug that Cook received, called bimagrumab, seems to counteract this muscle loss.

It’s one of more than 100 anti-obesity drug candidates that are in various stages of development. The next wave of medications, which are likely to hit pharmacy shelves in the next few years, resemble drugs that are already on the market. But close behind are numerous therapies being developed specifically for their muscle-sparing weight-loss potential. Dozens more are aimed at different biological pathways and could redefine obesity treatment in decades to come.

“We’re working to create the next generation of healthy weight-loss solutions,” says Philip Larsen, who played a key part in the early development of GLP-1 drugs and is now chief executive of SixPeaks Bio, an obesity-focused start-up company in Basel, Switzerland.

The surge in anti-obesity drug development has been made possible by the blockbuster success of semaglutide and its rival drug tirzepatide — sold as Zepbound or Mounjaro. These drugs have unlocked the potential for a global market that is projected to surpass US$100 billion by the end of the decade.

But semaglutide and tirzepatide have limitations. They require weekly injections and frequently cause unpleasant side effects, with nausea, vomiting and diarrhoea being particularly common. Long term, the loss of muscle mass and the likelihood of weight regain after stopping therapy are also issues. What’s more, the drugs don’t work sufficiently for an estimated 10–30% of people who take them.

Emerging therapies aim to amplify weight loss, improve tolerability, ensure long-lasting effects and find options for a broader range of individuals (see ‘Next up in obesity drugs’). “We’re going to see that there are different medicines that work better for different groups of people,” says Louis Aronne, an obesity specialist at Weill Cornell Medicine in New York City who consults for drug makers.

Next up in obesity drugs

Expected dates of US approval for new types of weight-loss drugs heading to market.

Estimated year	Drug	Company	Description
2026	Orforglipron	Eli Lilly	An oral, small-molecule drug that activates the glucagon-like peptide 1 (GLP-1) receptor.
2026	CagriSema	Novo Nordisk	An injectable that activates the amylin and GLP-1 receptors.
2027	Survodutide	Boehringer Ingelheim	An injectable that activates the glucagon and GLP-1 receptors.
2027	Retatrutide	Eli Lilly	An injectable that activates GLP-1, gastric inhibitory polypeptide (GIP) and glucagon receptors.
2028 and beyond	MariTide	Amgen	An injectable that activates the GLP-1 receptor while blocking GIP signalling.
2028 and beyond	Bimagrumab	Eli Lilly	An injectable that blocks receptors involved in myostatin signalling.
2028 and beyond	Monlunabant	Novo Nordisk	An oral drug that inhibits the CB1 cannabinoid receptor.

Diverse routes, same pursuit

Semaglutide and tirzepatide are often lumped together under the umbrella of GLP-1 drugs, but they differ in one key regard: tirzepatide mimics not only GLP-1 but also a complementary hormone called gastric inhibitory polypeptide (GIP). This hormone further revs up energy metabolism and affects how the body stores and burns nutrients. Tirzepatide’s dual action is thought to contribute to its superior weight-loss results.

In a large head-to-head trial, sponsored by tirzepatide’s maker Eli Lilly in Indianapolis, Indiana, participants who took tirzepatide lost an average of 20% of their body weight, outpacing the 14% reduction achieved with semaglutide, which is produced by the pharmaceutical firm Novo Nordisk in Bagsværd, Denmark. “We believe there’s a homeostatic mechanism, like a thermostat, that we each have that is set to a certain body weight, and it’ll drive hunger until we achieve that,” says Dan Skovronsky, chief scientific officer at Eli Lilly. But, he says, drugs such as tirzepatide can override this natural mechanism.

Inspired by tirzepatide’s success, many companies are advancing other drugs that engage GLP-1 and GIP receptors. At least five tirzepatide-like therapies are progressing through clinical trials, with the first expected to hit the market by 2028. Patients and clinicians alike “need an array of options”, says Ron Renaud, chief executive of Kailera Therapeutics, a biotechnology start-up in Waltham, Massachusetts, which has a tirzepatide-like therapy in advanced-stage clinical testing.

In addition to dual activators, such as tirzepatide, there are also drug candidates such as MariTide (produced by the biopharmaceutical company Amgen in Thousand Oaks, California) that instead block GIP signalling while still activating GLP-1. It might seem counterintuitive that both approaches could work. But Jonathan Campbell, a metabolism researcher at Duke University in Durham, North Carolina, explains metabolism in terms of a vehicle’s fuel consumption on the motorway: pushing the accelerator hard, as with GIP activation, burns energy inefficiently, depleting resources faster than they can be replenished. Conversely, driving without fully releasing the handbrake creates constant friction, much like blocking GIP, which introduces inefficiencies by forcing the system to work harder to maintain speed.

“In terms of weight control, anything that makes you less efficient is going to be a positive,” says Campbell, who receives research funding from drug companies. But he cautions that the wider consequences of each strategy remain uncertain. Because GIP also plays a part in bone health, there are concerns that blocking GIP signalling could adversely affect bone health. There are also lingering questions about the long-term effects of drastic weight loss on the rest of the body, including on muscle, metabolic flexibility and organ health.

Although drugs such as semaglutide and tirzepatide have been shown to reduce the risk of stroke, heart attack and other cardiovascular problems, as well as alleviate sleep apnoea and improve liver function, they have also been tied to conditions such as arthritis and pancreatitis. The unknown risks, particularly in diverse populations and with prolonged use, lead some clinicians to favour established surgical solutions, such as bariatric surgery.

But uncertainty hasn’t dissuaded pharmaceutical companies from pursuing an expanding array of hormone targets. These include other gut-derived hormones such as peptide YY, which is known for its ability to make you feel full, and pancreas-released hormones such as glucagon and amylin, which could complement GLP-1–based therapies by boosting energy expenditure, stabilizing blood sugar levels and further suppressing appetite.

Working together

Many strategies in development target multiple pathways simultaneously. The combination therapy CagriSema, for example, pairs a long-acting analogue of amylin with semaglutide. Participants in a 68-week, phase III trial lost an average of nearly 23% of their body weight with this approach, according to Novo Nordisk, the company behind the drug.

If ongoing trials are successful, CagriSema, along with agents that combine GLP-1 and glucagon activity, such as survodutide from the pharmaceutical firm Boehringer Ingelheim in Ingelheim, Germany, could secure regulatory approval as early as 2026 or 2027. However, their impact might be eclipsed by yet another contender. In phase II testing, Eli Lilly’s retatrutide — dubbed ‘triple G’ for its ability to target GLP-1, GIP and glucagon receptors — delivered an average weight reduction of 24% after 48 weeks, setting a new benchmark for obesity treatments¹ (see ‘Shedding weight’).

Sources: Weg.: J. P.-H. Wilding *et al. N. Eng. J. Med*. **384**, 989–1002 (2021); Zep.: A. M. Jastreboff *et al. N. Engl. J. Med*. **387**, 205–216 (2022); Surv.: C. W. le Roux *et al. Lancet Diabetes Endocrinol*. 12, 162–173 (2024); Reta.: ref. 1; Orfo.: ref. 2; CagriSema: **go.nature.com/4hmabvt**; MariTide: **go.nature.com/41scez4**

Carel le Roux, a metabolic medicine specialist at University College Dublin who consults for several drug makers, says the findings suggest that “the more mechanisms we add, the more benefit we get”. Activating multiple pathways could allow for lower doses that achieve the same weight loss with fewer side effects.

Companies are also exploring alternatives to once-a-week injections, which can be difficult to incorporate into people’s routines and come with manufacturing challenges. Once-monthly injectables are in the works, but GLP-1 pills — led by a drug called orforglipron produced by Eli Lilly — could arrive first, hitting the market as soon as next year. In a phase II, 36-week study, participants lost up to 15% of their body weight with the once-daily oral option².

Less familiar targets

Although gut hormones continue to be the cornerstone of drug development for obesity, large-scale genetic sequencing has been one source of inspiration for emerging targets. In 2021, scientists at the biotech company Regeneron Pharmaceuticals in Tarrytown, New York, led an analysis of DNA from nearly 650,000 individuals and uncovered a rare gene variant linked to low body weight³. The following year, researchers at Alnylam Pharmaceuticals in Cambridge, Massachusetts, led a study that pinpointed a mutation in a gene called INHBE. The mutation is associated with low waist-to-hip ratio, a measure that reflects a healthier fat distribution in the body⁴. Companies are now trying to develop drugs that replicate the metabolic benefits of these genetic variants.

Old targets are also getting renewed attention. One example is the cannabinoid receptor CB1, originally pursued after researchers discovered its role in marijuana-induced appetite stimulation, commonly known as the munchies. In the late-2000s, a drug designed to counteract this effect was briefly sold in Europe as a weight-loss therapy. But inhibiting cannabinoid receptors in the brain was associated with an increased risk of depression, anxiety and suicidal thoughts in some people. The drug, known as rimonabant, was withdrawn from the market after less than three years, and rival companies abandoned similar candidates.

But George Kunos, a neuroendocrinologist at the US National Institute on Alcohol Abuse and Alcoholism in Bethesda, Maryland, never gave up on the cannabinoid-blocking strategy. Around 15 years ago, his team and others demonstrated in rodents that much of the anti-obesity effects of CB1 inhibitors came from metabolic pathways in the liver, muscle, pancreas and other organs outside the brain. If a drug such as rimonabant could be chemically modified to prevent it from crossing the blood–brain barrier, it might deliver metabolic benefits without the serious side effects.

Kunos’s laboratory created such a next-generation cannabinoid blocker, now known as monlunabant and being advanced by Novo Nordisk. Last year, phase II trial results indicated that monlunabant can still cause anxiety, irritability and sleep disturbances. Even so, Kunos predicts that drug makers will “arrive at a dose that causes significant weight reduction with acceptable levels of side effects”.