The Changing Landscape of Pediatric Endocrinology in Cystic Fibrosis: Insights From the Post-CFTR Modulator Era

Advances in cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy have markedly improved survival, pulmonary function, and nutritional status in individuals with cystic fibrosis (CF), resulting in a shifting disease landscape in which endocrine and metabolic complications play an increasingly prominent role. This review summarizes current knowledge of key endocrine comorbidities in youth with CF in the postmodulator era, with a focus on CF-related bone disease, CF-related diabetes, and obesity. CF related bone disease remains common and multifactorial in origin, involving chronic inflammation, malnutrition, hormonal disturbances, and direct effects of CFTR dysfunction on bone metabolism; early evidence suggests potential but inconsistent effects of CFTR modulators on bone mineral density and microarchitecture. In contrast, obesity is emerging as a novel and increasingly prevalent phenotype, likely driven by improved nutrient absorption and decreased energy expenditure, and is associated with growing cardiometabolic risk. CF-related diabetes continues to affect a substantial proportion of individuals with CF and is associated with worsened clinical outcomes. While CFTR modulators, particularly ivacaftor, have demonstrated improvements in insulin secretion, highly effective combination therapies such as elexacaftor/tezacaftor/ivacaftor show modest and variable effects on glycemic control without consistent improvement in β-cell function. Overall, the long-term endocrine consequences of CFTR modulator therapy remain incompletely understood, particularly in children. Ongoing longitudinal studies are needed to clarify these relationships and inform evolving screening and management strategies in this population.