The Oral GLP-1 Revolution: What Comes After Rybelsus?
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have reshaped the treatment landscape for type 2 diabetes-and more recently, obesity. Their powerful metabolic effects have made them a mainstay in guidelines, but injectable formats have long been a barrier for some patients.
That’s why the arrival of Rybelsus, the first oral GLP-1 RA, was seen as a milestone. Built on semaglutide and SNAC absorption technology, it opened the door to non-injectable incretin therapy.
However, Rybelsus may soon face competition. A new generation of oral GLP-1 and dual agonists is emerging, with the potential for easier dosing and greater weight loss.
This article reviews the most promising oral candidates in development-including orforglipron, VK2735, and DehydraTECH-tirzepatide-and compares their clinical and commercial potential to Rybelsus.
Read more about Rybelsus: What is Rybelsus
Why Oral GLP-1 Matters
While injectable GLP-1 receptor agonists have proven highly effective for both type 2 diabetes and obesity, many patients remain hesitant or unwilling to use needles regularly. This presents a significant barrier to long-term adherence, especially in primary care and early-stage treatment settings.
Oral GLP-1 therapies offer a solution, potentially expanding access and improving real-world effectiveness by enhancing convenience and patient preference. Clinical experience with Rybelsus has already shown that a pill form can achieve comparable glycemic control when taken correctly.
However, the challenge lies in formulation. GLP-1 molecules are peptides-fragile and easily broken down in the gastrointestinal tract. The SNAC technology in Rybelsus addresses this, but it comes with strict dosing rules (fasting state, limited water, delayed meals). These limitations have fueled the search for new oral formulations with better pharmacologic and user profiles.
On the business side, the potential is enormous. As demand for obesity and metabolic therapies explodes, oral GLP-1s are forecasted to drive a multi-billion-dollar market, with growth fueled by patients who prefer simplicity over injections.
This has led to rapid development of second-generation oral agents, some of which go beyond GLP-1 alone.
Orforglipron (Eli Lilly): The First Non-Peptide Oral GLP-1 Agonist
Among the most promising entries in the oral incretin race is orforglipron, a once-daily, non-peptide GLP-1 receptor agonist developed by Eli Lilly. Unlike semaglutide and other peptide-based agents, orforglipron is a small molecule-meaning it doesn’t rely on specialized absorption enhancers like SNAC, and is not degraded by digestive enzymes.
This opens the door to simpler dosing and more stable absorption.
In the ACHIEVE-1 phase 2 trial, orforglipron showed:
- Body weight reductions up to ~15% after 36 weeks, depending on dose
- Significant reductions in fasting glucose and HbA1c
- Favorable safety profile with mild-to-moderate gastrointestinal side effects (nausea, diarrhea)
Early comparisons with injectable GLP-1s suggest similar or better weight loss, but fewer serious GI events requiring discontinuation. Another major advantage: no fasting or water restrictions are needed-patients can take the pill with or without food.
Orforglipron is currently in phase 3 trials for both obesity and type 2 diabetes. Planned studies include head-to-head comparisons with Rybelsus and Zepbound, which will be critical for assessing competitive positioning.
With its novel structure, potent metabolic effects, and ease of use, orforglipron could become the first truly mainstream oral GLP-1-and a strong contender to surpass Rybelsus in both reach and revenue.
VK2735 (Viking Therapeutics): A Dual GIP/GLP-1 Pill in the Making
Building on the success of tirzepatide, Viking Therapeutics is developing VK2735, an oral dual agonist of the GIP and GLP-1 receptors. This approach mimics the mechanism of injectable tirzepatide (Zepbound/Mounjaro), which has shown superior weight loss and glycemic control compared to GLP-1 agonists alone.
What sets VK2735 apart is its oral formulation-designed to be taken once daily, without injections.
Phase 1 and 2a data showed:
- Weight loss of 7–10% over 13 weeks in adults with obesity
- Lower incidence of nausea and vomiting compared to injectable tirzepatide
- Promising glycemic improvements (full data pending)
Unlike semaglutide-based oral agents, VK2735 is structurally optimized for oral delivery and may avoid the need for absorption enhancers like SNAC. This could simplify administration and improve consistency of effects.
Viking is positioning VK2735 primarily as an anti-obesity therapy, though type 2 diabetes is also a potential future indication.
If late-stage trials confirm early promise, VK2735 could be a leading oral dual-agonist option-especially for patients avoiding injectables.
DehydraTECH-Tirzepatide: Reformulating the Gold Standard
Unlike orforglipron and VK2735, which are new chemical entities, DehydraTECH-Tirzepatide is an innovative formulation of an existing blockbuster: tirzepatide, the dual GIP/GLP-1 agonist marketed as Zepbound and Mounjaro. The company behind this effort, Lexaria Bioscience, isn’t developing a new active ingredient-instead, it’s focusing on enhancing absorption through its DehydraTECH™ delivery platform.
DehydraTECH is a lipid-based oral drug delivery technology designed to improve the bioavailability of lipophilic compounds. By encapsulating tirzepatide in a fat-soluble form, the platform may bypass enzymatic breakdown and facilitate intestinal absorption, potentially allowing for oral delivery of a drug traditionally given by injection.
Early-stage results have shown:
- Comparable bioavailability to subcutaneous tirzepatide at lower doses
- ~50% reduction in nausea incidence compared to injection
- Preliminary weight loss trends similar to injectable forms
A phase 2b trial is planned for 2025–2026, with obesity and type 2 diabetes as target indications.
If successful, this strategy could reshape how existing peptide-based therapies are delivered. Instead of inventing new drugs, companies could repurpose proven injectables into oral forms using DehydraTECH or similar platforms.
This approach may offer a lower-cost, faster-to-market pathway to meet the rising demand for non-injectable metabolic therapies.
Where Does Rybelsus Stand?
Rybelsus, developed by Novo Nordisk, remains the only approved oral GLP-1 receptor agonist on the market as of 2025. Its track record in glycemic control, cardiovascular safety, and real-world usage gives it a strong foothold in type 2 diabetes care.
Strengths:
- Robust clinical data from the PIONEER trial program, including significant HbA1c reductions (~1.0–1.5%)
- Cardiovascular safety confirmed in the SOUL trial (2025), with a 14% reduction in major adverse CV events
- Widespread availability and brand recognition
- Preferred choice for patients who reject injectables and need early glycemic control
Limitations:
- Strict dosing regimen due to SNAC: must be taken on an empty stomach with water and no food for 30 minutes
- Modest weight loss (~4–5%), limiting appeal in obesity-focused care
- Competing innovations promise simpler use and more potent weight loss
New contenders like orforglipron and VK2735 offer potentially easier administration and greater efficacy in weight reduction-especially relevant in the growing obesity market.
While Rybelsus may retain its leadership in type 2 diabetes, its position in the broader metabolic arena could weaken if next-gen oral GLP-1s prove both clinically superior and easier to use.
Rybelsus remains the pioneer-but its future dominance is no longer guaranteed.
Market Forecast Through 2028
The global market for GLP-1-based therapies is expanding rapidly, fueled by rising prevalence of obesity and diabetes, as well as increasing demand for weight-loss medications. As oral alternatives to injectable incretin therapies become viable, analysts project the oral GLP-1 market alone could reach $15–20 billion by 2028.
Likely Market Dynamics:
- Rybelsus will likely maintain a strong position in the type 2 diabetes segment, backed by its established safety, brand trust, and broad availability. Its role in obesity, however, may be increasingly marginalized due to modest weight loss and strict dosing requirements.
- Orforglipron appears poised to dominate the oral obesity segment, with phase 3 data expected to confirm its high weight-loss efficacy and convenient administration. Lilly’s commercial engine behind Zepbound gives it a major head start in brand development and payer negotiations.
- VK2735 and DehydraTECH-Tirzepatide may initially target niche markets, especially among patients seeking non-injectable options with dual-hormone action. If tolerability advantages hold up in late-stage trials, they could disrupt standard formulations.
Looking ahead, the oral GLP-1 space may split into three tiers:
- Rybelsus for diabetes-first patients,
- Orforglipron for general weight management, and
- Next-gen dual agonists for high-risk, high-need populations.
Technology, tolerability, and patient-centric convenience will drive adoption and shape the competitive landscape over the next three years.
Conclusion
Oral GLP-1 therapies are rapidly emerging as a cornerstone in the next phase of treating metabolic diseases. While Rybelsus has led the way, the field is evolving quickly, with non-peptide agents like orforglipron and dual agonists like VK2735 and DehydraTECH-tirzepatide introducing new levels of convenience, tolerability, and effectiveness.
Each candidate brings distinct advantages: better weight loss, simplified dosing, or dual-mechanism efficacy. Their success will depend not only on clinical performance, but also on patient preference, cost-effectiveness, and market access.
Rybelsus may retain a key role in early type 2 diabetes care, but its supremacy is being challenged-especially in the obesity market. The next 2–3 years will likely define which therapies become standards of care, and which fade into the background.
For now, the oral incretin pipeline is robust-and the race to lead this category has only just begun.
References
- SOUL Trial: Oral semaglutide significantly reduced MACE in patients with type 2 diabetes and established cardiovascular or kidney disease. Link
- ACHIEVE-1 Trial: Orforglipron led to up to 14.7% weight reduction in patients with obesity. Link
- Lilly Phase 3 Press Release: Link
- VK2735 Phase 2 Trial Launch: Link
- VK2735 Subcutaneous Data: Link
- DehydraTECH-Tirzepatide Oral Data: Link
- GLP-1-H24-4 Human Study Update: Link