Once-Monthly and Extended-Interval Incretin-, Amylin-, and THRβ-Targeting Therapies for Type 2 Diabetes and Obesity: Clinical Evidence and Development Pipelines

Once-monthly injectable therapies targeting glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and adjacent metabolic pathways are moving from a conceptual goal to a plausible next step for type 2 diabetes (T2D) and obesity. The most clinically advanced program is maridebart cafraglutide (MariTide), a long-acting GLP-1 receptor agonist conjugated to an Fc-containing scaffold that also mediates sustained GIP receptor antagonism. Across phase 2 trials, once-monthly maridebart has produced clinically meaningful weight loss (~12–16% in adults without diabetes; ~8–12% in those with T2D), together with HbA1c reductions of ~1.2–1.6 percentage points, with a safety profile broadly consistent with GLP-1-based therapy. An exploratory every-8-weeks regimen showed attenuated efficacy, suggesting that monthly dosing may represent a practical lower boundary for maintaining therapeutic exposure and metabolic effect in this format. Beyond maridebart, a rapidly expanding pipeline—including ultra-long-acting GLP-1 analogs, dual GLP-1/GIP agonists, long-acting GIPR antagonists, amylin receptor agonists, and emerging thyroid hormone receptor beta (THRβ) agonists—is actively testing monthly regimens or induction-to-monthly maintenance strategies; however, most readouts remain early and are frequently limited to conference presentations or sponsor communications. Accordingly, much of the pipeline evidence should be interpreted as early-phase and non-peer-reviewed, and therefore hypothesis-generating. Key uncertainties include long-term durability, cardiometabolic outcomes, immunogenicity, and interindividual variability in response, which will ultimately determine how once-monthly regimens integrate with established weekly standards in routine care.