New Era for Weight Loss? Oral GLP-1 Drugs Are On the Horizon

A groundbreaking announcement from Eli Lilly has sent ripples through the metabolic disease community: the company’s oral small-molecule GLP-1 receptor agonist, orforglipron, has delivered impressive results in its phase 3 trial for type 2 diabetes. Not only did it lower HbA1c levels by an average of 1.3%–1.6%, but participants in the high-dose group also lost an average of 7.9% of their body weight in just 40 weeks.

This could mark a historic shift: the wildly popular “injectable weight loss drugs” might finally enter the market as easy-to-take oral pills.

Over the past few years, GLP-1-based drugs like semaglutide (sold as Ozempic and Wegovy) have dominated the obesity and diabetes markets due to their dual ability to reduce weight and regulate blood glucose. Originally a gut-secreted hormone released after meals, GLP-1 helps suppress appetite and control blood sugar—but its natural form is unstable and degrades quickly in the body. Structural modifications in semaglutide prolong its half-life and boost GLP-1 receptor activation in the pancreas, CNS, and gut. The drug increases insulin secretion, inhibits glucagon release, slows gastric emptying, and signals satiety in the brain, making it effective for both diabetes management and weight reduction.

Figure 1. Mechanism of GLP-1 Receptor Agonists in Weight Management

Unlike traditional anti-diabetic or appetite suppressant medications, GLP-1 agonists offer a multi-target metabolic approach—positioning semaglutide as one of the most talked-about anti-obesity drugs of the decade.

Challenges of Peptide-Based GLP-1 Drugs

However, these injectable drugs have drawbacks: they require cold-chain storage, involve injections, and are expensive to manufacture. As peptide molecules, they are unstable in the digestive tract and cannot be absorbed via oral administration. While Novo Nordisk introduced an oral version of semaglutide in 2019, it still requires high doses, an empty stomach, and absorption enhancers—posing inconvenience for long-term use.

This has fueled interest in oral small molecules, which are easier to manufacture and absorb. The pharmaceutical industry has been seeking ways to mimic GLP-1 agonism with non-peptide compounds.

Figure 2. Small-molecule GLP-1 agonists bind to the same receptor site as larger peptide hormones

The challenge? Achieving precise binding to the complex active site of the GLP-1 receptor. In 2017, cryo-EM studies revealed the receptor’s 3D structure, opening new doors for structure-based drug design. Orforglipron is a result of this breakthrough—it fits tightly into the receptor’s “pocket,” mimicking peptide-like activation of downstream signaling pathways. Although Pfizer’s danuglipron showed promise initially, development was halted due to liver toxicity concerns. Other companies like Ambrosia and Septerna are now exploring new binding domains and combination therapies to achieve improved efficacy and safety.

Future Trends: Multi-Target Oral GLP-1 Therapies

Drugs like tirzepatide (Zepbound/Mounjaro), which combine GLP-1 and GIP receptor agonism, have demonstrated even greater weight-loss potential. The next wave of oral weight loss medications is likely to feature multi-target strategies: GLP-1 + GIP, GLP-1 + Glucagon, or even precision-targeted polypharmacology. Though technical hurdles remain, the future clearly lies in small-molecule, orally bioavailable, multi-targeted anti-obesity therapeutics.

Recommended Research Tools from abinScience

As GLP-1 drug development evolves from peptides to small molecules, from single targets to dual and multi-targeted approaches, the need for precise research tools becomes ever more critical. abinScience offers high-quality reagents to support GLP-1 related studies, including antibodies, proteins, and ELISA kits:

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