Incretin treatment selection should consider comorbidity, expected weight loss, durability, route, tolerability, body composition, and access. This review evaluated phenotype-oriented evidence for semaglutide, tirzepatide, and emerging oral or multi-agonist therapies.

PRISMA 2020 and PRISMA-S informed a focused narrative review. PubMed/MEDLINE, Embase, Scopus, Web of Science, CENTRAL, trial registries and citation sources were searched with bibliographic coverage from 1 January 2024 to a final search date of 8 January 2026, and supplementary searches without a lower date limit. Two reviewers screened records and extracted data independently. Risk of bias and certainty of evidence were appraised descriptively rather than through formal RoB 2, ROBINS-I or GRADE procedures.

Twenty-eight report-level sources were included (22 primary analyses and 6 contextual sources). Tirzepatide produced greater weight loss than semaglutide in SURMOUNT-5; semaglutide reduced major cardiovascular events in SELECT. Both improved outcomes in obesity-related heart failure with preserved ejection fraction, while tirzepatide improved obstructive sleep apnea outcomes and reduced diabetes onset in prediabetes. Semaglutide and tirzepatide showed phase 3 and phase 2 metabolic dysfunction-associated steatohepatitis (MASH) results, respectively. Discontinuation in routine care was common.

Treatment should follow phenotype and a sustainable plan rather than an average weight-loss hierarchy. Cost, route, adverse effects, reproductive plans, persistence, and muscle function should inform selection. Biomarker-guided algorithms remain investigational.