The Future of GLP-1: Quad Agonists, Oral Formulations, and Extended-Interval Analogues

The clinical and commercial success of Semaglutide and Tirzepatide has triggered the most intensive incretin pipeline in pharmaceutical history. Three structural directions are now driving research: increasing the number of receptors targeted, moving from injection to oral delivery, and extending dose intervals from weekly to monthly. Each has compounds in active clinical development.

From Mono to Quad Agonists

The progression is straightforward in principle: each additional receptor target adds a complementary metabolic mechanism.

• Mono (GLP-1 only): Liraglutide, Semaglutide. Approximately 8% (SCALE) to 15% (STEP 1) body-weight reduction in trials ^[1,2].
• Dual (GIP + GLP-1): Tirzepatide. Up to about 21% (20.9% at the highest dose) in SURMOUNT-1 ^[3].
• Triple (GIP + GLP-1 + glucagon): Retatrutide. Approximately 24.2% at 48 weeks in Phase 2 ^[4].
• Four or more targets: So far mainly preclinical; for example, a single molecule acting on the GLP-1 and GIP receptors plus three PPAR receptors was tested in obese mice in a 2026 study ^[5].

Quad Agonist Candidates

Agonists with four or more targets remain at an early stage of development. Hanmi Pharmaceutical's HM15275, sometimes discussed in this context, is a long-acting GLP-1, GIP and glucagon triple agonist rather than a quad agonist: Phase 1 results presented in 2025 reported favourable safety and tolerability with supportive trends in weight and glycaemic control, and a Phase 2 trial is under way (Hanmi, November 2025). Adding amylin signalling is a separate strategy being pursued by combination products such as Cagrisema, which pairs Semaglutide with Cagrilintide, an amylin analogue ^[6].

Why More Targets Is Not Automatically Better

Adding receptors increases mechanistic breadth but also increases risk of off target effects, manufacturing complexity, and regulatory uncertainty. Glucagon receptor activation, for example, must be carefully balanced because excess activity raises blood glucose. Retatrutide was designed with balanced glucagon and GLP-1 receptor activity and greater GIP receptor activity; in obese mice, its glucagon receptor activity added an increase in energy expenditure to the reduced food intake driven by the incretin components ^[7].

Oral GLP-1 Peptides

Oral delivery removes the largest patient barrier to incretin therapy. Two approaches are progressing.

Oral Semaglutide (Rybelsus) is already approved, formulated with the absorption enhancer SNAC. Bioavailability is below 1% (estimated at 0.8%) ^[8], requiring a substantially higher oral dose to approximate the systemic exposure of an equivalent subcutaneous injection.

Higher-dose oral Semaglutide has been studied in the OASIS programme and produced a mean weight reduction of 15.1% at 68 weeks in OASIS 1 ^[9], comparable to injectable Semaglutide in STEP 1 ^[2]. This established that oral peptide GLP-1 therapy can match injectable efficacy at the cost of higher mass delivered.

Orforglipron is a non peptide small molecule GLP-1 receptor agonist from Eli Lilly. As a small molecule, it does not require absorption enhancers and can be taken without food restrictions. Phase 2 data published in NEJM in 2023 reported weight reductions of up to 14.7% at 36 weeks ^[10]. In the Phase 3 ATTAIN-1 trial, the highest dose produced a mean reduction of 11.2% at 72 weeks versus 2.1% with placebo ^[11], and the US FDA approved orforglipron for adults with obesity, or overweight with weight-related medical problems, in April 2026 (Lilly, April 2026).

Monthly and Ultra Long Acting Injectables

Reducing dose frequency from weekly to monthly improves adherence and reduces injection burden. Several strategies are in development:

• Albumin binding extensions: Adding fatty acid chains that bind to circulating albumin to extend half life. Semaglutide already uses this principle: its design increased albumin affinity relative to Liraglutide, supporting a once-weekly rather than once-daily schedule ^[12].
• Fc fusion proteins and antibody conjugates: Linking GLP-1 agonists to immunoglobulin Fc domains or antibodies extends half life. Efpeglenatide, an exendin-based agonist, was given once weekly in the AMPLITUDE-O outcomes trial, which found fewer cardiovascular events than placebo ^[13], and the peptide-antibody conjugate maridebart cafraglutide has been tested once monthly in a Phase 2 trial ^[14].
• Implantable depots: Vivani Medical's NPM-115 is a small implant designed to release Exenatide steadily over an extended period; its Phase 1 study, LIBERATE-1, compared it with weekly injectable GLP-1 agonists over 9 weeks and completed in 2025.

What This Means for Researchers

The peptide research market is rapidly diversifying beyond the established Semaglutide and Tirzepatide reference compounds. Laboratories conducting comparative receptor binding, pharmacokinetic, or formulation studies are increasingly working with Retatrutide, Cagrilintide, and emerging quad agonist sequences. Quality requirements remain consistent across the class:

• HPLC purity not less than 99% for receptor binding work
• Mass spectrometry confirmation of molecular weight, including any fatty acid modifications
• Documented synthesis route, particularly for compounds with non standard amino acids or lipidation
• Endotoxin below 0.5 EU/mg for any cell based application

Outlook

The GLP-1 class now includes an approved daily oral small molecule, and by 2028 it may also include an approved triple agonist and an approved monthly injectable. Quad agonists and depot implants are strong candidates for the following wave. The defining trend is no longer whether incretin therapy works, but how to deliver progressively more efficacious mechanisms with progressively lower patient burden.

References

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