Beyond GLP-1: the next wave of weight-loss medication innovation

“There is a real sense now of a rapid expansion in the area of novel medications in the area of obesity,” says Hannah Beba, pharmacist and clinical lead for obesity at West Yorkshire Integrated Care System. 

Amira Guirguis, pharmacy professor and chair of the Science and Research Committee of the Royal Pharmaceutical Society, agrees: “I think weight loss has always been the aim of so many people, and [now] it’s about access to medicine.”

While the pharmaceutical giants behind Wegovy (semaglutide; Novo Nordisk), Mounjaro (tirzepatide; Eli Lilly) and others race to expand their cardiometabolic portfolios, innovative approaches that promise more effective weight loss or fewer side effects could set new therapies apart.

Looking at the pipelines set out by major manufacturers, The Pharmaceutical Journal highlights some of the most promising and most novel approaches that could be rolled out to patients in the years to come, unpacking how they work and what benefits they could offer. 

Incretin therapies

The first generation of weight-loss medications are incretin therapies that regulate insulin secretion, building on type 2 diabetes mellitus (T2DM) treatments utilising glucagon-like peptide-1 (GLP-1) receptor agonists.

“These drugs are new to us, but they’ve been at least a decade in development for diabetes,” says Katrina Bicknell, professor of pharmacology and pharmacy education at Reading School of Pharmacy.

Semaglutide and liraglutide fall into this category and work by targeting GLP-1 receptors: increasing insulin, decreasing glucagon and delaying gastric emptying — making patients feel fuller for longer. Wegovy is licensed in the UK in doses up to 2.4mg for weight loss and, on 14 September 2025, Novo Nordisk published results of a phase IIIb clinical trial (‘STEP UP’, NCT05646706) of a 7.2mg dose of semaglutide for subcutaneous injection^​1​.

GLP-1s can offer weight loss of more than 15% — a substantial amount that could make a real difference to comorbidities associated with obesity, such as cardiovascular outcomes, Guirguis says.

Adding gastric inhibitory polypeptide (GIP) receptor agonists amplifies the gastric effects of GLP-1s, as the higher weight loss promised by the dual action tirzepatide, compared with semaglutide, exemplifies^​2​.

Retatrutide (Eli Lilly), a triagonist currently in phase III clinical trials (TRIUMPH-1 NCT05929066 and others^​3​) adds a glucagon receptor agonist to its mechanism of action, promising an even greater impact on weight loss. Novo Nordisk is also investigating a triple agonist of GLP-1, GIP, and glucagon receptors; and a once-weekly subcutaneous tri-agonist^​4​.

Meanwhile, Pfizer is developing an oral GIP analogue, currently known as PF-07976016, which is to be administered daily. In December 2024, a phase IIa dose-ranging trial (NCT06717425) to investigate this drug began, and is due to end in December 2025^​5​.

Most incretin weight-loss therapies are injected subcutaneously, but oral semaglutide is already licensed in the UK for T2DM as Rybelsus, while its manufacturer Novo Nordisk has published positive phase III results (‘OASIS-4’, NCT05564117) for its 25mg semaglutide pill for weight loss^​6​.

Orforglipron (Eli Lilly) is also an oral GLP-1 RA administered as a once-daily pill for weight loss.

Bicknell says an oral formulation of a protein is “really exciting” from a pharmacological perspective, as well as offering greater accessibility for patients. 

According to Sehar Shahid, a pharmacy owner in Scotland, oral formulations will be easier to store and transport than current injectable pens, increasing access for patients.

She also notes that tablets typically cost less than injectable formulations, but stresses that patients should be offered “the most appropriate medication for them… it shouldn’t be driven by a financial gain”.

Jayne Hornung, chief clinical officer at Managed Markets Insight and Technology, suggests initial pricing of oral GLP-1s for weight loss could be “reminiscent of the early days of anti-CGRP medications for migraines … when the first oral CGRP came to market in 2019, the pricing still remained high”. This could lead to slower uptake, she suggests.

Orforglipron

Eli Lilly published the results of its ‘ATTAIN-1b’ trial for obesity in September 2025^​7​, which compared orforglipron to placebo in more than 3,100 adults without diabetes, with a BMI of 30+ or 27-30 with an obesity-related complication — including hypertension, dyslipidaemia, cardiovascular disease or obstructive sleep apnoea — and a history of at least one patient-reported unsuccessful dietary effort to lose body weight, who have tried unsuccessfully to lose weight with diet alone. Results suggest orforglipron leads to significant weight loss, at an average of 7.5% of body weight over 72 weeks for those on a 6mg dose, which increased to 8.4% with 12mg and 11.2% with 36mg, compared with 2.1% with placebo.

These weight-loss measurements are lower than those recorded for other GLP-1 drugs, such as semaglutide, which are reported to result in mean weight reductions of 15–20% and beyond. 

Participants also recorded reductions in waist circumference (average 7.1cm loss on 6mg, 8.2cm on 12mg, 10cm on 36mg, compared with 3.1cm loss on placebo), blood pressure (estimated -4.2 and -1mm HG difference between placebo and orforglipron in systolic and diatolic blood pressure, respectively) and cholesterol (-2.1% difference between placebo and orforglipron).

Retatrutide

Phase III results for retatrutide are set to be released later in 2025 and in early 2026, but an earlier phase II trial recorded between a 7.2% and 17.5% reduction in body weight after 24 weeks, depending on the dose (7.2% on 1mg, 17.5% on 12mg), and up to a 24.2% reduction in body weight after 48 weeks for those on 12mg (-8.7% change for those on 1mg)^​8​.

At the highest doses, retatrutide seems to promise more significant weight loss than existing GLP-1s on the market — but as dosage increases, so does the risk of side effects, mostly mild-to-moderate gastrointestinal issues, although one case of pancreatitis occurred in a patient on the 12mg dose during the phase II trial.

Retatrutide is still unavailable outside of clinical trials, but that has not stopped a surge in illegal activity around the drug, with people claiming to buy and sell it on social media. 

Incretin antagonists

While incretin agonists, such as GLP-1s, activate hormone receptors in the gut, other drugs — known as antagonists — take the approach of shutting down certain functions.

One such drug is Amgen’s Maridebart cafraglutide (MariTide, formerly AMG 133). Unlike tirzepatide, which activates both GLP-1 and GIP receptors, MariTide is a GIPR antagonist antibody/GLP-1R peptide agonist conjugate — which means that it activates GLP-1 receptors while blocking GIP responses.

Emerging evidence suggests that GIPR antagonism could improve the tolerability of agonists by reducing nausea, according to a 2025 study^​9​.

In a statement published alongside the results, Amgen said “it used its genetic expertise to identify GIP receptor inhibition as a key factor in reducing body mass, an insight that led to MariTide’s development”.

MariTide

In a phase II study, MariTide demonstrated weight loss of up to approximately 20% in people living with obesity without T2DM, compared with 2.6% in the placebo group and up to approximately 17% in those who have obesity and T2DM^​10​.

In a statement published alongside the results, Amgen said: “Weight loss had not plateaued by 52 weeks, indicating the potential for further weight reduction.”

It added that improvements were recorded across other cardiometabolic measures, including waist circumference, blood pressure, high-sensitivity C-reactive protein (hs-CRP) and select lipid parameters.

Gastrointestinal adverse events were “predominantly limited to initial dosing”, while dose escalation resulted in lower discontinuation rates owing to these adverse events than among patients who remained on the starting dose.

The drug has a long half-life, which means it can be administered monthly or less frequently, giving the drug “the potential to improve adherence and long-term weight control”, according to Jay Bradner, executive vice president of research and development at Amgen.

Amgen’s statement added that the long half-life, combined with its dual mechanism of action, means the drug “may allow for greater durability or reduce the likelihood of weight regain after treatment stops”.

Amylin therapies

Some drugs currently in development take a different approach, targeting receptors for a different hormone: amylin, which is co-secreted, alongside insulin, by the pancreas to slow gastric emptying, suppress glucagon secretion and signal feelings of fullness.

Eloralintide (Eli Lilly) acts as a selective amylin receptor agonist and is administered once weekly as a subcutaneous injection. A phase II trial is underway in the United States (NCT06916065) to evaluate tolerance and side effects^​11​. 

Novo Nordisk is currently investigating two amylin agonists, as well as oral [SC20] amycretin (NCT06049329^​12​) and subcutaneous amycretin (NCT06064006^​13​) — a long-acting co-agonist of GLP-1 and amylin.

Amylin’s offering closest to market is CagriSema, which combines its successful GLP-1 receptor agonist semaglutide with cagrilintide, an amylin analogue. CagriSema is intended for once-weekly subcutaneous treatment.

Cagri Sema

In a Novo Nordisk funded study of 3,417 adults without diabetes and with a BMI of 30 or higher, or a BMI of 27 or higher with at least one obesity-related complication, participants achieved an average 20.4% weight loss with cagrilintide–semaglutide, compared with –3.0% with placebo^​14​.

Guirguis says combination treatments such as this could offer “additive or synergistic effects” — meaning that patients have a better chance of responding to at least one of the mechanisms and could experience fewer GI side effects as a result of the dual approach.

Other approaches

Obesity is a widespread and heterogeneic disease that will require “a variety of approaches”, manufacturer Amgen has said, revealing that it is developing both oral and injectable approaches, comprising both incretin and non-incretin mechanisms.

Meanwhile, Eli Lilly has told The Pharmaceutical Journal that its next wave of research would be “focused on the potential of tailoring therapies to patient subgroups through biomarkers and precision medicine to understand who benefits most from each mechanism”.

Guirguis says any new therapy needs to be “cost effective, safe, efficacious”, have good bioavailability, have a simple dosing regimen and “get patients’ acceptability and affordability”. 

New developments should target some of the problems associated with existing treatments, such as muscle mass lost on GLP1s, she suggests.

Meanwhile, existing treatments for other conditions could be repurposed for weight loss. “All the companies are trying to have an edge over the other companies,” Guirguis says.

New mechanisms for weight loss are continually being explored, offering new potential drug targets — from cannabinoid receptor blockers, nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inhibitors, free fatty acid receptor 2 (FFA2) inhibitors and gene-editing RNA therapy.

Monlunabant

Monlunabant is a small molecule that blocks CB1 receptors, which is intended for oral administration. It was designed to treat obesity by targeting peripheral receptors, but some researchers believe it might actually exert its effects through CB1 receptors in the central nervous system^​15​.

Results of a phase IIa trial published in 2024 demonstrated that a once-daily 10mg, 20mg and 50mg dose of monlunabant all led to statistically significant weight loss compared with placebo after 16 weeks. The 10mg dose led to weight loss of 7.1kg compared with a 0.7kg loss on placebo, while limited additional weight loss was recorded with higher doses of monlunabant^​16​.

In addition to gastrointestinal side effects, participants also reported mild-to-moderate neuropsychiatric issues, primarily anxiety, irritability and sleep disturbances. These were more frequent and dose dependent with monlunabant compared with placebo.

A previous CB1 receptor blocker, Rimonabant, was approved in Europe in 2006 but was discontinued in 2008 owing to serious psychiatric side effects.

Non-pharmacological interventions

FUSE

Perhaps Novo Nordisk’s most novel offering is a once-monthly ultrasound treatment for obesity, currently in early stages of exploration as part of a collaboration with GE Healthcare.

Announcing the collaboration in 2023, GE HealthCare said peripheral focused ultrasound therapy — which uses ultrasound to activate the nervous system, stimulating nerve pathways to produce effects such as increased glucose metabolism — has potential as a non-invasive, non-pharmacological alternative for chronic disease management.

Wraparound support

New therapies for weight loss mean more choice for patients, eventually resulting in lower prices and more personalised approaches.

“I think pharmacists need to be educated around precision medicine, because I think weight management is not ‘one size fits all’. It’s about a personalised approach,” says Guirguis.

“When we talk about obesity, we need to account for gender, for age, for body composition – for example, fat versus muscle. We need to redefine obesity and ensure that pharmacists understand the problem that they are trying to solve.”

Guirguis says that data should be collected in order to develop predictive models about what to expect in certain patient populations. For Bicknell, data on the long-term effects will also be valuable. 

Both clinicians stressed the importance of understanding the psychological side of attitudes towards food and weight loss.

“Obesity is multi-factorial. You don’t become obese just simply because you eat too much. Of course, you have the dietary pattern, but you also have the physical activity. You have sleep patterns. You have some medications that can cause you weight gain, genetically, you may be prone to put on more weight. And of course, there are a lot of environmental factors that can also affect weight gain,” she says.

Reena Patel, a pharmacist and healthcare strategy consultant, advocates for a “trauma-informed approach” when managing people who have obesity.

“It is incredibly important as a healthcare system that we start treating obesity as a long-term condition and wrap care around people living with obesity, which may include diet, lifestyle, psychological support and, for some people, medication to help them manage and lower their weight.”