Multi-agonist GLP-1, GIP, amylin, and glucagon therapies achieve >20% weight loss and resolve obesity complications

Obesity is a chronic relapsing disease linked to significant morbidity, mortality, and healthcare costs. Current pharmacotherapies often fall short in achieving substantial, sustained weight reduction and addressing the full spectrum of obesity-related complications. There's a critical need for treatments that not only induce significant weight loss but also provide broad metabolic and organ-specific benefits, shifting care towards a phenotype-guided, complication-centric approach.

This systematic review identified articles published between 2021 and 2026 via a Medline search using MeSH terms and keywords related to new-generation obesity pharmacotherapy. Reference lists of relevant reviews were also screened. The review included Phase 2 and 3 clinical trials evaluating emerging obesity pharmacotherapies in adults, specifically those reporting outcomes like weight loss and improvements in obesity-related complications.

Entero-pancreatic hormone-based therapies targeting GLP-1, GIP, amylin, and glucagon pathways demonstrated substantial efficacy beyond just weight reduction. While GLP-1 based agents achieved approximately 10-15% weight loss, agents targeting multiple pathways showed greater efficacy. For instance, Tirzepatide, CagriSema, and amycretin achieved weight reductions exceeding 20%. The triple agonist retatrutide produced even greater reductions, exceeding 25%. Beyond weight loss, these agents significantly improved glycemia and supported diabetes prevention. They also produced organ-specific benefits:

Reduced cardiovascular events, improved heart failure symptoms, decreased obstructive sleep apnea severity, improved metabolic dysfunction-associated steatohepatitis, slowed chronic kidney disease progression, and reduced osteoarthritis-related pain.