Contemporary incretin-based therapy has shifted obesity management from ranking drugs by mean weight loss alone toward selection based on dominant comorbidity, treatment persistence, route preference, tolerability, body composition, and the consequences of withdrawal.

To synthesize evidence supporting phenotype-oriented selection of semaglutide, tirzepatide, oral incretin strategies, and triple GIP, GLP-1, and glucagon agonism in adults with obesity or overweight and clinically relevant comorbidity.

A focused systematic review was conducted according to PRISMA 2020. MEDLINE, Embase, Scopus, Web of Science Core Collection, and CENTRAL were searched for evidence published from 1 January 2024 to 8 July 2026. Two reviewers independently screened records, extracted data, and assessed risk of bias.

Twenty-eight studies or contextual documents were included. Tirzepatide showed the strongest direct comparative weight-loss signal; semaglutide had mature cardiovascular and phase 3 hepatic evidence. Both agents had randomized evidence in obesity-related HFpEF.

Phenotype-oriented selection is better supported than a single hierarchy based on weight loss. Route, cost, tolerability, persistence, reproductive plans, and muscle function should be incorporated into treatment planning.