(229) Impact of cystic fibrosis transmembrane conductance regulator(CFTR) modulator therapy on nutritional status, hepatic steatosis, and dyslipidemia

Background: Cystic fibrosis (CF) is a common genetic disorder that occurs due to a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR). CF classically affects the lungs, causing progressive pulmonary disease, but also manifests in disease of the pancreas, liver, intestine, and reproductive organs. CFTR modulators are a novel class of medications that restore CFTR function for people with certain CFTR variants. Tezacaftor/ivacaftor(Symdeko) and lumacaftor/ivacaftor (Orkambi) are CFTR modulators that were introduced between 2015-2018 and provide modest improvement in CFTR function. Elexacaftor/tezacaftor/ivacaftor(Trikafta) was approved in 2019 and is highly effective at restoring CFTR function. It also dramatically improves lung function and can treat a wider array of CFTR mutations [1]. The impact of CFTR modulators on lipid levels, triglycerides, and hepatic steatosis, has not been well characterized [2].

Methods: Thirty adults with cystic fibrosis underwent abdominal MRI to assess the protein density fat fraction (PDFF) while treated with no modulator, a not highly effective modulator (Tezacaftor/ivacaftor or lumacaftor/ivacaftor), or the highly effective modulators (Elexacaftor/tezacaftor/ivacaftor). Retrospective chart review was used to evaluate BMI and ppFEV1 within 3 months of the MRI. Serum lipids were recorded if it was taken within a one-year time period from the MRI with same modulator status.

Results: Eight patients had data available before and after highly effective modulator therapy. Eight patients had data available on no modulator and on any modulator treatment. A paired Mann Whitney test was used to compare pre and post treatment data. Comparing pre and post Elexacaftor/tezacaftor/ivacaftor, there are significant increases in median ppFEV1 from 68% to 78% (p=0.0156) and in median BMI from 22.7 to 24.7 kg/m² (p=0.0078) after the addition of Trikafta. There are also significant increases in median LDL-C from 73 to 90 (p=0.0078) and median HDL-C (p=0.0391) from 48 to 52 after the addition of Trikafta. There are no statistically significant changes of PDFF and triglycerides (TG). Comparing no modulator versus any modulator, there is a statistically significant increase in median BMI from 21.8 to 24.7 (p=0.031). The median HDL- C also increases from 46 to 52 with approaching statistical significance (p=0.0625). There are no statistically significant changes in ppFEV1, PDFF, LDL-C, and TG.

Conclusions: This study showed that treatment with the highly effective CFTR modulator, Elexacaftor/tezacaftor/ivacaftor, is associated with an increase of HDL-C, LDL-C, and BMI. Hepatic steatosis did not consistently change as patients transitioned between modulator status. This study was limited by the number of patients that got pre and post scans with lipid levels performed within one year. Further research should investigate the mechanisms of higher lipid levels in cystic fibrosis after modulator treatment, and whether this incurs a higher risk for cardiovascular disease.

Acknowledgements:

References: [1] Lindblad, A., Glaumann, H., & Strandvik, B. (1999). Natural history of liver disease in cystic fibrosis. Hepatology (Baltimore, Md.), 30(5), 1151–1158. https://doi.org/10.1002/hep.510300527



[2] Cuevas-Ocaña, S., Laselva, O., Avolio, J., & Nenna, R. (2020). The era of CFTR modulators: improvements made and remaining challenges. Breathe (Sheffield, England), 16(2), 200016. https://doi.org/10.1183/20734735.0016-2020