The therapeutic landscape for obesity management is rapidly evolving. While glucagon-like peptide-1 (GLP-1) receptor agonists like semaglutide and tirzepatide (a dual GIP/GLP-1 agonist) have revolutionized care, the pipeline is advancing toward novel mechanisms offering potential for enhanced efficacy, tolerability, and convenience. For the healthcare professional, understanding these emerging targets is key to anticipating future treatment paradigms.
The current focus extends beyond the incretin pathway to include poly-agonist therapies, activators of energy expenditure, and entirely new mechanistic classes.
- Next-Generation Poly-agonists
The success of tirzepatide demonstrated the superior efficacy of targeting multiple hormonal pathways. The next wave includes molecules that agonize three or more receptors.
Retatrutide (LY3437943): This Lilly molecule is a triple agonist targeting the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors (so called Triple G). The glucagon component is theorized to enhance energy expenditure and lipolysis. A study published in the New England Journal of Medicine showed a mean weight reduction of 24.2% at 48 weeks with the highest dose (12 mg), suggesting a potent step-change in efficacy. Further data is imminent.
CagriSema: This Novo Nordisk combination is a fixed-dose co-formulation of the GLP-1 agonist semaglutide and the long-acting amylin analogue cagrilintide. Amylin is a hormone that contributes to satiety, delays gastric emptying, and suppresses postprandial glucagon secretion. Data indicates additive effects, with weight loss comparable to or potentially exceeding that of tirzepatide.
- Non-Incretin Pathways: Novel Mechanisms of Action
Research is exploring pathways independent of the traditional incretin system to address limitations like side effects and weight plateaus.
Bimagrumab: This novel monoclonal antibody blocks activin type II receptors (ActRII), primarily inhibiting myostatin. This promotes significant increases in lean body mass while reducing adipose tissue. This approach could potentially mitigate the loss of lean mass commonly seen with incretin therapies, a critical consideration for long-term metabolic health and physical function. Phase 2 data is promising.
GCGR/GLP-1R Dual Agonists: While retatrutide includes GCGR, other candidates like mazdutide are also exploring this dual target. The glucagon agonism is designed to boost hepatic energy expenditure and reduce fat storage, potentially offering a different efficacy and side effect profile compared to GIP/GLP-1 targets.
- Oral Biologics and Formulation Advances
The burden of weekly injections is a barrier for some patients. Several companies are developing oral formulations of GLP-1 agonists, but true innovation lies in oral biologics that target new pathways.
Oral GLP-1 Agonists: While oral semaglutide exists for diabetes, its weight loss efficacy at higher doses and broader applicability are areas of active development.
Small Molecule Amylin Mimetics: Companies are developing oral formulations of amylin analogues. Success in this area could provide a non-injectable option for enhancing satiety and glycemic control.
Clinical Considerations and Future Outlook
For the clinician, these emerging therapies signal a move toward highly personalised obesity medicine. The future may involve:
Sequencing and Combination: Using agents with complementary mechanisms (e.g., an incretin for weight loss combined with a myostatin inhibitor for lean mass preservation).
Tolerability Management: New targets may offer alternatives for patients who cannot tolerate the GI effects of GLP-1-based therapies.
Beyond Weight Loss:Evaluating therapies based on composition of weight loss (fat vs. lean mass) and impacts on cardiometabolic health, NAFLD, and physical function.
While these agents are still under investigation, they underscore a fundamental shift: obesity pharmacotherapy is moving beyond single-hormone mimicry toward integrated, multi-system approaches that more closely mimic the body’s complex physiology of weight regulation.
