GLP-1 receptor agonists show promise as orthogonal metabolic candidates for Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Autosomal dominant polycystic kidney disease (ADPKD) is a leading genetic cause of kidney failure, primarily driven by mutations in PKD1 or PKD2 genes. Current treatment with vasopressin V2-receptor antagonism (tolvaptan) decelerates progression but has adherence limitations and doesn't address all disease biology. Emerging evidence suggests metabolic reprogramming, mitochondrial dysfunction, and visceral adiposity significantly modify cyst growth and eGFR decline, representing an unmet therapeutic need beyond cAMP-centered control.

This review synthesizes mechanistic, human, and trial-design evidence to evaluate the potential of GLP-1 receptor agonists (GLP-1RAs) in ADPKD. The authors examined studies on cystic bioenergetics, human phenotype modifiers of progression, and metabolism-oriented interventions. They also incorporated recent direct data on semaglutide in Pkd1 animal models and analyzed the design logic of ongoing early-phase clinical trials (e.g., NCT06582875) to assess GLP-1RAs as orthogonal metabolic candidates for disease modification.

The review concludes that GLP-1 receptor agonists (GLP-1RAs) are plausible candidates to engage adiposity-related and metabolic stress pathways that contribute to ADPKD progression heterogeneity. They are not mechanistic surrogates for tolvaptan but offer a complementary approach. Evidence includes insights from cystic bioenergetics, where impaired fatty-acid oxidation and mitochondrial dysfunction are implicated in cyst growth. Observational human data link obesity and visceral adiposity to modified kidney-volume expansion and eGFR decline. > Recent preclinical data demonstrated that semaglutide directly impacted Pkd1 models, suggesting a beneficial effect on cyst growth and kidney function. The authors highlight that GLP-1RAs could address residual risk factors beyond cAMP control, offering a novel therapeutic avenue.