Autosomal dominant polycystic kidney disease (ADPKD) remains therapeutically anchored to vasopressin V2-receptor antagonism, yet progression heterogeneity and persistent unmet need increasingly suggest residual disease biology beyond cAMP-centered control. Converging experimental and observational human phenotype data suggest that metabolic reprogramming, mitochondrial dysfunction, impaired fatty-acid oxidation, obesity, and visceral adiposity may modify cyst growth, kidney-volume expansion, eGFR decline, or treatment-response heterogeneity, although causal and therapeutic evidence remains incomplete. In this review, we synthesize mechanistic, human, and trial-design evidence-from studies of cystic bioenergetics and human phenotype modifiers of progression to metabolism-oriented interventions, recent direct semaglutide data in Pkd1 models, and the design logic of ongoing early-phase clinical evaluation-to examine whether GLP-1 receptor agonists deserve consideration as orthogonal metabolic candidates for translational disease modification in ADPKD. Across these lines of evidence, GLP-1 receptor agonists should be viewed not as mechanistic surrogates for tolvaptan, but as plausible candidates to engage adiposity-related and metabolic stress pathways that may contribute to progression heterogeneity. At the same time, the field remains at an early translational stage, with important uncertainties regarding patient selection, trial enrichment, endpoint selection, co-administration with tolvaptan, and safety monitoring. GLP-1-based therapy should not currently be regarded as a treatment for ADPKD; rather, the available evidence supports a phenotype-aware translational program in which metabolic burden, visceral adiposity, and residual risk beyond tolvaptan guide early clinical testing and endpoint selection.
