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The shift from injection to ingestion. Small molecule GLP-1s are rewriting the obesity playbook.
While injectables (Semaglutide/Tirzepatide) currently dominate, the future is oral. Small molecule GLP-1 agonists (unlike peptide-based Rybelsus) do not degrade in the stomach, allowing for higher bioavailability, cheaper manufacturing, and mass adoption without needles.
Status: Phase 3 Trials
Class: Non-peptide Small Molecule
Efficacy: ~14.7% weight loss at 36 weeks.
Advantage: Can be taken with food (unlike Rybelsus).
Status: Reformulating (Phase 2b)
Class: Non-peptide Small Molecule
Challenge: Twice-daily dosing caused high nausea rates; reformulating to once-daily.
Status: FDA Approved
Class: Oral Semaglutide (Peptide)
Limit: Requires SNAC technology to survive stomach acid. Strict fasting window (30m) required.
Next-Gen: Novo is testing 25mg and 50mg Rybelsus (vs current 14mg max) to rival injectable efficacy (15%+ loss).
| Feature | Injectable (Wegovy/Zepbound) | Oral (Small Molecule) |
|---|---|---|
| Dosing Frequency | Weekly | Daily |
| Bioavailability | 100% | High (Small Molecule) / Low (Peptide) |
| Food Requirements | None | Depends (Rybelsus: Strict Fasting) |
| Cost to Manufacture | High (Biologic) | Low (Chemical Synthesis) |
| Side Effects | GI Distress | GI Distress (potentially higher nausea) |
Note: Small molecule GLP-1s are potent chemicals, not bio-identical peptides. Long-term safety data is still emerging compared to 20+ years of peptide data.