Long‐term impact of Elexacaftor/Tezacaftor/ivacaftor on pulmonary, nutritional and metabolic outcomes in homozygous F508del cystic fibrosis patients: A real‐world cohort study

Aim Elexacaftor/tezacaftor/ivacaftor (ETI) has markedly improved cystic fibrosis (CF) outcomes. However, its long‐term impact on nutrition, metabolism and liver health remains underexplored. We assessed 30‐month changes in pulmonary, nutritional, metabolic and inflammatory markers in people with CF (PwCF) homozygous for F508del. Methods We retrospectively analysed 112 PwCF (median age‐31 years) treated with ETI from July 2021 to December 2024. Clinical, spirometric and biochemical data were collected at baseline and at 6, 12, 24 and 30 months. Results ETI produced sustained lung function gains (percent predicted FEV₁ + 15 points at 24 months, p < 0.001), BMI increase (+1.7 kg/m 2 in year‐one, p < 0.001) and marked C‐reactive protein reduction (−80% at 6 months), with an 85% decrease in pulmonary exacerbations. Nutritional recovery shifted BMI distribution: underweight prevalence declined from 12.5% to 1.8%, while overweight rose from 15.2% to 27.7%. Adolescents improved in weight‐for‐age Z‐scores (+0.42, p = 0.01). Total and LDL cholesterol increased but remained within reference ranges; HDL, triglycerides and glycaemic control stayed stable, with no new cystic fibrosis–related diabetes (CFRD). Vitamin D improved; vitamin B12 fluctuated with supplementation. Mild, transient transaminase elevations occurred in 4.5% of PwCF, with no fibrosis progression (APRI/FIB‐4 below risk thresholds). Conclusion ETI provides durable multisystem benefits, preserving lung function and improving nutritional and metabolic profiles. However, the shift towards overweight/obesity and biochemical signs of hepatic stress suggests evolving cardiometabolic risks. These findings support early ETI initiation and reinforce the need for ongoing monitoring of nutrition, lipid profile and liver function, together with updated CF care strategies to mitigate long‐term cardiometabolic complications.