Once-Monthly Semaglutide: Hydrogel Microspheres Could Replace Weekly Injections
Semaglutide attached to hydrogel microspheres achieved a 36-day release half-life in mice, producing equivalent weight loss to twice-daily dosing and potentially enabling once-monthly human administration with a lower peak-to-trough ratio.
Quick Facts
What This Study Found
Hydrogel microsphere-semaglutide showed an in vivo release half-life of ~36 days in mice. A single subcutaneous dose produced 20% lean-sparing body weight loss over one month, statistically equivalent to twice-daily semaglutide. Pharmacokinetic simulations predicted once-monthly human dosing with Cmin matching weekly dosing but only 75% of the Cmax, potentially reducing adverse effects.
Key Numbers
Cleavable linker designed for ~1 month in vivo release half-life. Single subcutaneous dose tested in mice.
How They Did This
Semaglutide conjugated to hydrogel microspheres via a cleavable linker (designed for ~1 month release half-life). Single subcutaneous dose administered to diet-induced obese mice. Pharmacokinetic parameters and bodyweight measured. Results used to simulate human PK for once-monthly dosing. Compared to semaglutide administered twice daily in mice.
Why This Research Matters
Weekly semaglutide injections are a barrier for some patients. A monthly formulation that maintains the same therapeutic minimum while reducing peak drug levels could improve adherence and potentially reduce the gastrointestinal side effects (nausea, vomiting) that cause many patients to discontinue treatment.
The Bigger Picture
This addresses one of the major limitations of current GLP-1 peptide therapy — injection frequency. If once-monthly dosing can match weekly efficacy while reducing peak-related side effects, it could expand the patient population willing and able to use these transformative medications.
What This Study Doesn't Tell Us
Mouse study — PK translation to humans is estimated, not proven. The 'lean-sparing' weight loss claim needs verification in human metabolic studies. Manufacturing scalability of hydrogel microspheres not demonstrated. Long-term safety of the hydrogel carrier not assessed. Human clinical trials needed.
Questions This Raises
- ?Will the predicted lower Cmax actually translate to fewer GI side effects in humans?
- ?Could this technology enable even less frequent dosing (every 2-3 months)?
- ?How does the manufacturing cost of hydrogel microsphere formulations compare to standard injectable semaglutide?
Trust & Context
- Key Stat:
- 36-day half-life A single injection of hydrogel microsphere-semaglutide released the drug over 36 days in mice, matching the weight loss of twice-daily semaglutide
- Evidence Grade:
- Rated preliminary: proof-of-concept mouse study with PK simulations for humans. No human clinical data. Published in PNAS, lending credibility to the approach.
- Study Age:
- Published in 2024 in PNAS. Represents a significant advancement in long-acting peptide formulation technology.
- Original Title:
- The limitation of lipidation: Conversion of semaglutide from once-weekly to once-monthly dosing.
- Published In:
- Proceedings of the National Academy of Sciences of the United States of America, 121(47), e2415815121 (2024)
- Authors:
- Schneider, Eric L, Hangasky, John A, Fernández, Rocío Del Valle, Ashley, Gary W, Santi, Daniel V
- Database ID:
- RPEP-09223
Evidence Hierarchy
Frequently Asked Questions
Could semaglutide become a once-monthly injection?
This study shows it's possible — by attaching semaglutide to slowly dissolving hydrogel microspheres, researchers achieved month-long drug release in mice with the same weight loss as daily dosing. Human trials would be needed to confirm this works in people.
Would monthly semaglutide have fewer side effects?
Simulations suggest the monthly formulation would maintain the same minimum therapeutic level as weekly dosing but with only 75% of the peak concentration. Since nausea and GI side effects are often related to peak drug levels, this could mean fewer side effects.
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Cite This Study
https://rethinkpeptides.com/research/RPEP-09223APA
Schneider, Eric L; Hangasky, John A; Fernández, Rocío Del Valle; Ashley, Gary W; Santi, Daniel V. (2024). The limitation of lipidation: Conversion of semaglutide from once-weekly to once-monthly dosing.. Proceedings of the National Academy of Sciences of the United States of America, 121(47), e2415815121. https://doi.org/10.1073/pnas.2415815121
MLA
Schneider, Eric L, et al. "The limitation of lipidation: Conversion of semaglutide from once-weekly to once-monthly dosing.." Proceedings of the National Academy of Sciences of the United States of America, 2024. https://doi.org/10.1073/pnas.2415815121
RethinkPeptides
RethinkPeptides Research Database. "The limitation of lipidation: Conversion of semaglutide from..." RPEP-09223. Retrieved from https://rethinkpeptides.com/research/schneider-2024-the-limitation-of-lipidation
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.