Beyond Semaglutide and Tirzepatide: The Next Wave of Obesity Medicines

The Endocrine Society's September 2026 scientific statement identified treatment-response heterogeneity, health outcomes, and medication safety among the major research gaps confronting a rapidly expanding obesity drug pipeline.¹ In an interview with Patient Care Online, Daniel J. Drucker, MD, a professor in the Department of Medicine at the University of Toronto and corresponding author of the statement, discussed investigational retatrutide, amylin-based regimens, oral agents, and glucagon/GLP-1 combinations that could broaden obesity treatment beyond semaglutide and tirzepatide. The central questions, Drucker said, were whether these therapies would provide distinct benefits, remain acceptably safe, or help patients who did not achieve the results they sought with current medicines.

Retatrutide activates GIP, GLP-1, and glucagon receptors. In a phase 2 trial involving 338 adults with obesity, participants receiving the highest studied dose had a mean weight reduction of 24.2% at 48 weeks, compared with 2.1% with placebo.² Those findings warranted further study and did not establish comparative safety or clinical outcomes against approved obesity medicines. Drucker also cautioned against treating investigational products obtained outside a regulated trial as equivalent to approved drugs. Approval status and source were important considerations when counseling patients who asked about pipeline medicines.

The conversation then moved to possible indications beyond weight management, particularly substance use disorders. Drucker described reduced interest in alcohol or tobacco reported by some patients but stressed that anecdotes could not establish efficacy or support an indication. A small phase 2 randomized trial provided an early signal: 48 adults with alcohol use disorder received semaglutide or placebo over nine weeks, with the study reporting reductions in some alcohol craving and drinking measures.³ Its size, duration, and selected population limited conclusions about clinical use.

New drugs and new uses could eventually change obesity care, but head-to-head comparisons, adverse-event data, and indication-specific trials were needed to determine who might benefit and at what cost. The September 2026 statement presented precisely these uncertainties as an agenda for research, not a forecast of approvals.¹

Relevant disclosures for Drucker include Amgen, Alnylam, AstraZeneca Inc, Crinetics, Eli Lilly, General Medicines Inc, Kallyope, Metsera, Pfizer Inc, Protagonist Therapeutics Inc, Roche, and Sanofi and speaking fees from Novo Nordisk Inc.

References

1. Jastreboff AM, Drucker DJ, Ard JD, et al. Obesity science, research gaps, and opportunities in the new era of obesity medicines: an Endocrine Society scientific statement. Endocr Rev. Published online September 9, 2026. doi:10.1210/endrev/bnag025
2. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity - A phase 2 trial. N Engl J Med. 2023;389:514-526. doi:10.1056/NEJMoa2301972
3. Hendershot CS, Bremmer MP, Paladino MB, et al. Once-weekly semaglutide in adults with alcohol use disorder: a randomized clinical trial. JAMA Psychiatry. 2025;82:395-405. doi:10.1001/jamapsychiatry.2024.4789