Beyond efficacy: the treatment lifecycle of incretin and multi-receptor agonists

Incretin and multi-receptor agonist therapies have delivered the widest range of cardiometabolic benefit of any pharmacological class in a generation, with documented benefit across obesity, type 2 diabetes, cardiovascular and renal outcomes, heart failure with preserved ejection fraction, obstructive sleep apnea, and metabolic-dysfunction-associated steatohepatitis. A substantial fraction of the cardiovascular benefit is weight independent. The pivotal trial evidence is now mature, extending to the dedicated tirzepatide cardiovascular outcome program. The clinical and system-level processes that govern long-term cardiovascular and metabolic benefit, however, lie largely outside the efficacy envelope that these trials measure. Real-world persistence is approximately one-third at 12 months in non-diabetic obesity. Discontinuation is dominated by cost rather than therapeutic failure. Weight and cardiometabolic gains revert toward baseline within months of abrupt cessation. Cyclical use has emerged as a common real-world pattern among adults who discontinue and then restart therapy. Our review proposes a lifecycle framework that organizes the evidence along the patient journey from initiation through titration, on-treatment trajectory, adverse-event landscape, persistence, discontinuation, and reinitiation. Tirzepatide serves as the analytical center of gravity; the selective GLP-1 receptor agonist literature serves as the mature comparator. Seven analytical positions are advanced, and five specific trial designs are named as the research agenda the field requires, four of which remain unaddressed. The work ahead is to align trials, prescribing pathways, and access systems with the chronic-pharmacotherapy reality of the class.