A new generation of weight-loss drugs move beyond GLP-1

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as Wegovy and Ozempic, have taken the food industry by storm. With the potential to significantly change consumer eating habits, they are forcing the industry to think about nutrient-dense foods catering for those with smaller appetites.

But the industry has only scratched the surface of what these drugs can do. A new range of drugs, currently in the research phase, aim to solve bottlenecks from the original wave.

Many of them don’t just target the GLP-1 hormone, but go beyond this.

Orforglipron: Orally administered GLP-1 drugProduced by Eli Lilly, this will be an orally administered drug. An article by the journal Nature predicts that it will be available by 2026.

The drug is Eli Lilly’s first nonpeptide GLP-1 receptor agonist, and can be taken orally, once-a-day.

The drug is still in the clinical trial phase. One clinical trial, for instance, has led to a 14.7% mean weight reduction among those involved over the course of the 36-week trial.

The company is confident in the drug, reported Reuters last week, stockpiling $550m (€525.3m) worth of ‘pre-launch inventory’.

Pills, being both more cost-effective and more appealing to the consumer, are something of a holy grail for weight-loss drug companies, and many are working on developing something similar.

CagriSema: Activating amylin and GLP-1 receptors CagriSema from Novo Nordisk activates both GLP-1 and amylin receptors. It is currently the subject of several clinical trials testing whether it can be used for overweight or obesity. It is injectable and, according to Nature, the estimated year of its US approval is 2026.

“CagriSema is an investigational fixed-dose combination of a long-acting amylin analogue, cagrilintide 2.4 mg, and semaglutide 2.4 mg. Novo Nordisk is investigating the two molecules to determine if they induce weight loss by reducing hunger, increasing feelings of fullness and thereby help people eat less and reduce their calorie intake,” a spokesperson for Novo Nordisk explains.

Amylin is a pancreas-related hormone that, in addition to further suppressing appetite, has the potential to stabilise blood sugar levels and boost energy expenditure.

Participants in one 68-week trial, according to Novo Nordisk, lost almost 23% of their body weight on average.

Also read → What GLP-1 drugs are already on the market?Survodutide: Dual GLP-1 and glucagon receptor agonist Produced by the German company Boehringer Ingelheim, alongside Zealand Pharma, Survodutide is an injectable drug that activates both the glucagon and GLP-1 receptors. According to Nature, the drug is predicted to be available in 2027.

As well as GLP-1 receptors, the drug activates glucagon receptors. According to one study, this resulted in the drug’s improved efficacy, compared with semaglutide, as glucagon receptor agonism in the liver and adipose tissue resulted in increased energy expenditure.

Glucagon receptors promote fat breakdown, as well as inhibit low blood sugar levels.

Alongside its use for overweight and obesity, studies of the drug focused on treating non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH), a condition where fat builds up in the liver.

Retatrutide: The ‘benchmark’ for weight lossRetatrutide, produced by Eli Lilly, also activates glucagon receptors, alongside GLP-1 receptors and gastric inhibitory polypeptide (GIP) receptors, which helps regulate blood glucose and nutrient balance (leading to the drug being dubbed the ‘triple G’ for activating these three receptors).

The drug is an injectable. According to Nature, it may be available in 2027.

Nature explains that, in trials, the drug has been found to reduce weight by an average of 24% over 48 weeks, making it a ‘benchmark’ for weight-loss drugs.

The drug has also, reports Reuters, significantly reduced blood lipid levels and cardiovascular risk at early stages. The drug had also reduced apoC-III, a protein partly responsible for glucose metabolism and inflammation, by 38%.

One researcher, Beverly Tchang, suggested that using multiple pathways, as Retatrutide does, is the best way forward due to obesity’s complexities.

MariTide: Weight-loss without a ‘weight-loss plateau’ MartiTide is a once-monthly injectable drug. Developed by Amgen, MariTide is, according to Nature, likely to be ready by 2028 at the earliest, although it could be significantly longer.

The drug, according to a spokesperson for Amgen, has the potential to provide weight loss without a ‘weight-loss plateau’, meaning that there won’t be a point when your weight-loss begins to plateau, and people can retain weight loss several months after they stop taking it (a key bottleneck in previous weight-loss drugs).

The drug has the potential to continue weight-loss beyond a 52-week limit.

While inducing GLP-1, the drug also reduces GIP activity. According to metabolism researcher Jonathan Campbell, GIP can use resources ineffectively, whereas blocking it means the system will be forced to work harder.

Nevertheless, there are potential downsides in blocking GIP, as it has a key role in bone health. As will all the drugs listed here, research is still ongoing.

A new generation of weight-loss drugs are moving beyond GLP-1 (Carolina Rudah/Getty Images)Bimagrumab: Reducing fat and retaining muscleBimagrumab, a drug developed by Eli Lilly, aims to help those taking it reduce fat whilst retaining muscle.

In the case of many previous GLP-1 drugs, the reduction of calories, as a result of the drug, leads to an energy deficit, causing the body to burn muscle as a response. Bimagrumab aims to provide the benefits without the drawbacks.

It aims to do this, according to Reuters, by preventing the activity of a protein called myostatin, which negatively regulates skeletal muscle mass.

According to Nature, it is only one of a great many therapies being developed aiming to help weight loss but keep muscle.

Monlunabant: A treatment for obesityDeveloped by Novo Nordisk, Monlunabant is not a GLP-1 receptor agonist at all, but a treatment for obesity. Instead, it focuses around the cannabinoid CB1 receptor.

“Monlunabant is an investigational inverse agonist of the CB1 receptor which plays an important role in metabolism and appetite regulation in the central nervous system as well as in peripheral tissues such as adipose tissues, the gastrointestinal tract, kidneys, liver, pancreas, muscles and lungs. CB1 plays an important role in appetite regulation and cardiometabolic pathways,” explains the Novo Nordisk spokesperson.

A previous drug blocking the receptor, known as rimonabant, had led to depression, anxiety and even suicidal thoughts, and was thus withdrawn from the market after less than three years. However, research is currently being done to explore whether it can be modified so as to not cross the blood-brain barrier.

Monolunabant is still a work-in-progress, but aims to take advantage of the appetite-suppressing effects of CB1 without the dangerous side effects.

Sourced From: Nature

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

Published on: 12 February 2025

Doi: https://doi.org/10.1038/d41586-025-00404-9

Authors: E. Dolgin

Sourced From: Nature

‘The weight-loss drugs being tested in 2025: will they beat Ozempic?’

Published on: 6 February 2025

Doi: https://doi.org/10.1038/d41586-025-00376-w

Authors: G. Guglielmi