^{Carole Kerzic, RPh, is a principal drug information pharmacist at Prime Therapeutics and executive editor of several pipeline publications.}  

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The popularity and ever-expanding indications for glucagon-like peptide-1 (GLP-1) receptor agonist drugs have soared in recent years. Several key developments in the drug pipeline could impact current trends and ultimately drive competition for these innovative medications.  

The next few months, and beyond, are shaping up to be a pivotal time for the GLP-1 landscape, as experts anticipate several new indication decisions from the United States (U.S.) Food and Drug Administration (FDA), including for metabolic dysfunction-associated steatohepatitis (MASH) and the first orally administered GLP-1 medicines for chronic weight management.  

While Prime’s clinical teams share a deep dive of what’s next in the GLP-1 pipeline in the quarterly GLP-1 Pipeline Update, let’s explore some of the top GLP-1 drug pipeline trends. 

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Which oral GLP-1s are awaiting FDA approval?  

At this time, no oral GLP-1 is FDA approved for weight loss. That could change in the fourth quarter of 2025, starting with semaglutide. Novo Nordisk announced that the FDA accepted a new drug application for a 25 mg oral version of semaglutide (Wegovy) for two new indications: 

1. Chronic weight management in adults living with obesity or who are overweight with at least one comorbid condition  
2. Reduce the risk of major adverse cardiovascular events (MACE) in adults with obesity or overweight with established cardiovascular disease (CVD). In the OASIS-4 trial, the 25 mg oral dose resulted in an average weight loss of 13.6% after 64 weeks  

Competition will likely heat up, as Eli Lilly is expected to submit its application to the FDA for the oral dual glucose-dependent insulinopropic polypeptide (GIP)/GLP-1 receptor agonist, orforglipron, by the end of 2025, with potential FDA approval in 2026. Orforglipron could also be set for FDA submission for type 2 diabetes management in 2026. 

Also in the pipeline, two oral GLP-1 drugs are in late-stage development: NA-931 (Bioglutide) and NA-941 from Biomed. Bioglutide regulates GLP-1, GIP, glucagon and insulin-like growth factor-1 (IGF-1). It’s in Phase 2b/3 trials for type 2 diabetes and weight management and weight-related comorbidities. Their other product, NA-941, regulates both GLP-1 and IGF-1 and is being evaluated in a Phase 2-/3 trial for the treatment of MASH. Timelines for potential FDA submission for NA-931 and NA-941 have not been announced. 

When it comes to treating type 2 diabetes,  semaglutide (Rybelsus) by Novo Nordisk is currently the only oral GLP-1 approved in the United States as an adjunct to diet and exercise to improve blood glucose, or glycemic control, in adults with type 2 diabetes. Maintenance treatment is one daily tablet (either the 7 mg or 14 mg strength). Novo Nordisk submitted its application to the FDA to expand the indication for Rybelsus to reduce the risk of MACE in patients with type 2 diabetes and established CVD and/or chronic kidney disease. This application is based on data from the SOUL cardiovascular outcomes trial that demonstrated a 14% relative risk reduction in MACE in patients treated with Rybelsus 14 mg orally once daily for approximately five years compared to those who received placebo. 

For most individuals, oral dosage forms offer a more convenient formulation compared to injections, especially for those who may not be comfortable with needles. Oral GLP-1s are typically taken once daily compared to once-weekly subcutaneous GLP-1 injections.  

Are any GLP-1s approved for MASH? 

MASH, formerly known as non-alcohol related steatohepatitis (NASH), is characterized by inflammation and damage of the liver caused by the accumulation of fat cells (steatosis) without significant alcohol consumption, which can lead to liver fibrosis (scarring), cirrhosis (severe scarring of the liver) and liver failure. Individuals with metabolic conditions such as type 2 diabetes and obesity are at an increased risk for developing MASH. There’s a considerable, unmet need around the treatment of MASH given rising cases and since resmetirom (Rezdiffra) is the only FDA-approved drug for this condition. 

Based on the association of MASH with diabetes and obesity, researchers are evaluating GLP-1s as a potential treatment option for MASH. GLP-1s lead to a decrease in the production of triglycerides and glucose, and an increase in glucose uptake, which ultimately may improve steatohepatitis, decrease fibrosis progression and reduce the risk of MASH complications.  

Novo Nordisk was granted a Priority Review for subcutaneous semaglutide (Wegovy) for the treatment of MASH. If approved, it will be the first GLP-1 to treat MASH, and an FDA decision is anticipated by the third quarter of 2025. Interim data from the ESSENCE trial revealed that 62.7% of patients treated with semaglutide had improved steatohepatitis and 37% had improved liver fibrosis compared to 34.1% and 22.5%, respectively, who received placebo. Basically, semaglutide helped patients improve their liver health more than no intervention did. 

Investigational GLP-1s that are in Phase 3 trials for MASH include survodutide from Zealand, Boehringer Ingelheim and NA-941. The first survodutide Phase 3 study in patients with MASH is estimated to be completed in June 2029, and the Phase 3 trial for NA-941 recently started.  

Are generic versions of GLP-1s available in the United States? 

In December 2024, several generic versions of liraglutide (Victoza) for the treatment of type 2 diabetes became commercially available in the United States, while an authorized generic (AG) version launched in the United States in June 2024. Victoza is indicated for the treatment of type 2 diabetes. 

In November 2024, the FDA approved Amneal’s generic version of AstraZenaca’s exenatide injection (Byetta). This is the first generic for the GLP-1 receptor agonist. Byetta is indicated as a addition to diet and exercise in adults with type 2 diabetes and is dosed twice daily via subcutaneous injection. Amneal launched its generic in late November 2024, while in October 2024, AstraZeneca announced that it will discontinue marketing of Byetta.  

Generics for liraglutide (Saxenda) and dulaglutide (Trulicity) could be available in 2027. Generics for other agents are expected sometime after 2027. 

We know that GLP-1s are associated with gastrointestinal (GI) side effects, such as  nausea and vomiting. Are there any drugs approved by the FDA to manage these adverse effects? 

Typically, GI side effects of GLP-1s — such as nausea and vomiting — are dose-dependent, mild-to-moderate in severity and occur mostly during initiation of therapy and up-titration. GI side effects of GLP-1s may be mitigated with appropriate dose escalation when initiating therapy. Patients prescribed a GLP-1 agent should also be encouraged to eat slowly, eat smaller meals and, if needed, adjust the timing of their GLP-1 dose in relation to food intake.  

While there are approved medications to treat nausea/vomiting for other conditions, there are no medications in the U.S. indicated specifically to treat GI side effects from GLP-1s. Neurogastrx is studying investigational metopimazine to reduce the incidence, duration and severity of nausea and vomiting associated with GLP-1s. Metopimazine is a dopamine D2 receptor antagonist that exerts its antiemetic effects via the chemoreceptor trigger zone, which mediates nausea and vomiting through peripheral receptors. Top-line results of the Phase 2 trial demonstrated metopimazine led to a 40% reduction in the incidence of nausea and a 56% reduction in frequency of vomiting in individuals who received a single subcutaneous dose of semaglutide. 

How is Prime staying ahead of the GLP-1 pipeline?  

Given the considerable continued growth expected in the GLP-1 pipeline, Prime’s team of clinical experts actively monitors this emerging landscape. One of the ways Prime stays ahead of the GLP-1 pipeline is through a dedicated quarterly publication, which captures the evolving GLP-1 pipeline and anticipated indications. We have had a terrific response to this material from our industry peers, so it’s gratifying work for our team.  

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Check out the latest trends in the May edition of Prime’s GLP-1 Pipeline Update and the Prime GLP-1 Strategy page for more information. 

^{All brand names noted are the property of their respective owners.}