What’s the outlook for GLP-1 therapeutics?

8 July 2026 • By Bruno Quinney • #Exclusive Content

Tagged Clinical trial, GLP-1, Obesity, Weight loss

Is the honeymoon period over for GLP-1s or is the market yet to reach its full potential? Diana Turner asks what will differentiate the next generation of these peptide analogues.

Glucagon-like peptide-1 (GLP-1) receptor agonists like semaglutide (Ozempic/Wegovy) and tirzepatide (Mounjaro/Zepbound), which is also a GIP (glucose-dependent insulinotropic polypeptide) receptor, have been hugely profitable for the pharmaceutical industry, first as diabetes therapies and then as obesity treatments. Indeed, the two dominant brands have taken their manufacturers into the top five pharma companies in the world – Eli Lilly sits in first place, while Novo Nordisk is at number five – mainly driven by the drugs’ use for weight loss. Research led by researchers at University College London has shown that an estimated 1.6 million adults in England, Wales and Scotland used GLP-1 agonists for weight loss between early 2024 and early 2025. In the US, nearly 12% have used GLP-1 drugs for weight loss, including about one-fifth of women aged 50 to 64, according to a new RAND report (1).

Overcoming access and supply issues

Oral formulations of the drugs are making GLP-1s accessible to ever more people. In December 2025, the US Food and Drug Administration (FDA) approved the Wegovy pill “to reduce excess body weight and maintain weight reduction long term and to reduce the risk of major adverse cardiovascular events”, making it the first oral GLP-1 to reach the market. It has been a huge success for Novo Nordisk, with sales outstripping even optimistic predictions. Then in April 2026, the FDA approved Eli Lilly’s oral drug Foundayo (orforglipron) for “adults with obesity, or overweight with weight-related medical problems”. The tablets have been touted as the next option after coming off injectables. Lilly’s Phase III ATTAIN-MAINTAIN trial found that the pills helped people maintain weight loss after switching from injectable incretins to oral GLP-1 therapy. A number of other oral GLP-1 candidates are currently in late-stage trials. Verdiva Bio, for example, has launched an ongoing Phase IIb study of its once-weekly oral GLP-1 VRB-101.

The drugs’ promise of quick and easy weight loss, alongside potential cardiovascular and other health benefits, have led to huge demand, and this has only intensified with the introduction of oral formulations. This has forced a move toward geographically diversified manufacturing networks to protect launches, stabilise supply, and sustain long-term market access across markets. Intelligence company GlobalData argues that the risk of rising Middle East geopolitical disruptions are reshaping pharmaceutical supply strategies, pushing obesity drugmakers to localise production, secure inventories, and build resilient Asia-focused capacity. Eli Lilly has set up new manufacturing plants in China and Japan, designed to strengthen local production for GLP-1 medicines, while conflict-related disruptions in the Middle East are sharpening industry focus on supply chain resilience and strategic stockpiling. The company has stockpiled around $1.5 billion in its orforglipron inventory ahead of a broader rollout ahead of the oral GLP-1 weight loss candidate. Meanwhile, Novo Nordisk is upgrading its Athlone, Ireland, site to produce tablet-form semaglutide for markets outside the US.

Edita Hamzic, Healthcare Analyst at GlobalData, says: “Lilly’s latest investments show that the GLP-1 market is no longer being shaped by demand alone. Companies are now building geographically segmented manufacturing networks to serve local markets, manage policy pressures, and protect against disruptions that could affect access to critical medicines.”

Next generation GLP-1s

Despite their popularity, GLP-1s cause muscle and bone-loss, as well as gastrointestinal side-effects that can be debilitating in some patients. There is also the risk of weight returning immediately after stopping the drugs. In January 2026, data published in the British Medical Journal showed that patients who come off weight-loss injections such as Mounjaro or Wegovy regain the weight four times faster than those who stop conventional dieting and exercising (2).

The need to mitigate side-effects is one factor driving the discovery of new treatment options. For Novo Nordisk, the threat of imminent patient expiry is also an influential factor. Semaglutide’s core patent expired on March 2026 in several major markets including India, China, Brazil and Canada, though in the US, the UK and many European countries, patent protections are expected to last until at least 2031.

Eli Lilly is investigating a first-in-class triple agonist, a drug that functions as a GIP, GLP-1 and glucagon triple hormone receptor agonist. Results from the Phase III TRANSCEND-T2D-1 in patients with type 2 diabetes, have shown that retatrutide delivered superior A1C reduction and weight loss at 40 weeks compared to placebo, using both the efficacy and treatment-regimen estimands. The drug also showed clinically meaningful improvements from baseline across key cardiovascular risk factors, including non-HDL cholesterol, triglycerides and systolic blood pressure. Then in May, the company has reported positive topline results from TRIUMPH-1, a Phase III clinical trial evaluating retatrutide in adults with obesity or overweight and at least one weight-related comorbidity without diabetes. At 80 weeks, the company says, all doses of retatrutide met the primary and key secondary endpoints for obesity, delivering clinically meaningful weight loss.

MetaVia is looking to enter this market, and has announced positive results from the Phase I clinical trial of DA-1726, a novel, dual oxyntomodulin (OXM) analogue agonist that functions as a glucagon-like peptide-1 receptor (GLP1R) and glucagon receptor (GCGR). The results show robust early weight loss, statistically significant reductions in waist circumference, strong improvements in glucose control, and meaningful reductions in liver stiffness, alongside a favourable safety and tolerability profile. At the start of 2026, another company, Alveus Therapeutics raised $159.8 million to advance ALV-100, a bifunctional fusion protein combining GIP receptor antagonism with GLP-1 receptor agonism, designed to deliver potent and sustained weight loss as well as long-term weight maintenance.

Meanwhile, in May 2026, Fractyl Health received Clinical Trial Application authorisation in the Netherlands to initiate the Phase I/II first-in-human study of RJVA-001, introducing a one-time treatment option into the GLP-1 landscape. RJVA-001 is the first adeno-associated virus (AAV)-based gene therapy candidate to enter clinical development for type 2 diabetes. It is delivered via an endoscopic ultrasound-guided infusion directly into the pancreas, where it harnesses an engineered version of the human insulin promoter and trafficking signals to drive nutrient-triggered secretion of GLP-1 from transduced pancreatic beta cells. “GLP-1 medicines have changed what is possible in obesity and type 2 diabetes, but they require chronic, high-dose systemic exposure that many patients cannot or do not sustain,” says Harith Rajagopalan, Co-Founder and CEO of Fractyl Health. “RJVA-001 takes a different path: a potential one-time, pancreas-targeted gene therapy designed to enable the body to produce GLP-1 in response to meals: physiology, not pharmacology.”

Combination treatments

Another way to manage the adverse effects of a drug is to mitigate these through combination with other treatments, and many companies are developing drugs that work alongside GLP-1s to improve weight loss but also the side effect profile. A March 2026 study makes the scientific case for combination approaches in obesity pharmacotherapy, highlighting the complex interplay between multiple gut‑brain pathways involved in energy regulation, appetite, and metabolic control (3). Drawing on existing evidence, the authors make the case that targeting multiple biological mechanisms offers a more comprehensive therapeutic strategy for managing obesity.

OrsoBio’s oral, liver-targeted mitochondrial protonophore TLC-6740 was shown to increase weight loss in combination with the GLP-1/GIP receptor agonist tirzepatide in a Phase Ib/IIa trial. At week 24, participants receiving TLC-6740 plus tirzepatide achieved mean weight loss of 13.3%, compared with 8.8% with tirzepatide alone. The combination produced significant improvements in insulin sensitivity, liver biochemistry, adiponectin, and hsCRP. An MRI substudy demonstrated meaningful reductions in liver fat and total, visceral, and skeletal muscle adiposity, with no adverse impact on lean mass. Antag Therapeutics’ novel GIPR antagonist has also shown promise when combined with cagrilintide and GLP-1 agonist liraglutide, demonstrating an additive effect on weight loss, body composition, insulin sensitivity and CV risk biomarkers.

Another hopeful, iBio is commencing a first-in-human clinical trial in Australia for its long-acting monoclonal antibody IBIO-600, which is designed to preserve lean mass and improve body composition alongside GLP-1 therapies. Martin Brenner, Chief Executive Officer and Chief Scientific Officer of iBio, expands: “While GLP-1 therapies have transformed the treatment landscape, significant gaps remain, particularly around the loss of muscle mass. We believe IBIO-600 has the potential to address this unmet need.”

Unfortunately, not all these combinations have shown a benefit. Novo Nordisk saw a significant fall in its stock value in early 2026 following disappointing trial results for CagriSema, a fixed dose combination of cagrilintide 2.4mg and semaglutide 2.4mg. Although CagriSema demonstrated 23% weight loss in the open-label head-to-head Phase III REDEFINE 4 trial, it did not meet the primary endpoint of showing non-inferiority compared to tirzepatide 15mg at 84 weeks.

Mark Bagnall, CEO, Phenomix Sciences, says trial failures like these reflect the lack of innovation in metabolic disease clinical trials: “Oncology shifted toward precision medicine years ago by identifying the specific genetic drivers of cancer before prescribing treatment. Obesity care is finally following suit by replacing generic clinical trials with targeted approaches based on specific genetic and metabolic phenotypes. For example, we now know that patients with different biological drivers of obesity, like hunger signalling or energy expenditure, can respond very differently to the same therapy. We’re actively reshaping how people think about obesity — not as a willpower problem, but as a condition with real, identifiable biological drivers that can be tested, targeted, and treated at the individual genetic level.”

Alternative weight loss treatments

With various other drugs in development designed as alternatives to GLP-1s or as follow-on treatments, there will be a number of new players entering the market in the coming years to challenge the GLP-1’s current dominance.

Two such new approaches to obesity are ARO-INHBE and ARO-ALK7, investigational RNA interference (RNAi) therapeutics developed by biotech company Arrowhead Pharmaceuticals. Preliminary results in Phase I/IIa trials have found meaningful reductions in visceral fat, total fat and liver fat, suggesting both candidates could be effective treatments for obesity and metabolic diseases either as monotherapies or in combination with GLP-1s. The clinical trial results also represent the first in-human demonstration that the Activin E/ALK7 pathway, a genetically validated pathway that regulates adipose fat storage, may potentially be harnessed therapeutically to improve body composition and enhance weight loss.

New research has indicated that obesity could be treated in other ways than using drugs like GLP-1s that suppress appetite (4). The study identifies how brown fat cells, which are linked to weight loss, communicate to expand nerve and blood vessel networks, boosting heat generation. The researchers used single-cell RNA sequencing to identify SLIT3, a protein secreted by brown fat cells, which is thought to play a role in how fat cells communicate. They also found that SLIT3 gene expression may regulate fat tissue health, inflammation, and insulin sensitivity in people with obesity, indicating that the processes involved in brown fat could be harnessed for their therapeutic potential.

The future of obesity treatment

Now the honeymoon period is over for GLP-1s, we are entering a more realistic phase in our relationship with these drugs.

HH Kim, CEO and President of MetaVia, writing for DDW, summarises the situation: “The first wave of GLP-1 therapeutics demonstrated that metabolic diseases can be treated far more effectively than once believed. The industry should be proud of the accomplishments and lives that have been changed. The second wave will determine which therapies deliver faster and more durable results, while addressing both obesity and the broader metabolic landscape.

“Over the next decade, actual progress in cardiometabolic medicine will be driven not by hype, but by differentiation. Companies that recognise this, whether through novel dual agonists, combination approaches, or more accessible delivery formats, will meet a market that is still in the early stages of reaching its full potential.”

A precision medicine approach, like that applied in oncology, could be the key to improving tolerability, overcoming supply issues and increasing clinical trial success rates in this crowded market. Data revealed by omics company Ovation.io and PrecisionLife have shown that biomarkers can predict the efficacy, safety and tolerability of GLP-1 therapies, shedding light on refined patient enrolment in clinical trials and the potential for a payor-facing test to inform reimbursement policy.

Phenomix’s Mark Bagnall concludes: “To succeed in this competitive landscape, drug developers must prioritise matching the correct medicine to the right patient. In our research, we’re already seeing meaningful variability in response, adherence, and discontinuation across patient populations, which underscores the limitations of a one-size-fits-all model. Ultimately, this precision approach will optimise how new therapeutics are developed, delivered to patients, and improve the health of many.”

References

From DDW Volume 27 – Issue 3, Summer 2026 – Read the digital issue here