Effect of elexacaftor/tezacaftor/ivacaftor therapy on serum lipoprotein functions in adults with cystic fibrosis

Abstract

Cystic fibrosis is a genetic and multisystemic disease associated with a very poor quality of life and life expectancy. The introduction of the combined treatment with elexacaftor/tezacaftor/ivacaftor (ETI, Kaftrio) has extended the life expectancy of adults with cystic fibrosis (awCF), which could have an impact on the prevalence of certain chronic diseases, such as cardiovascular (CV) diseases. In this regard, in a recent work, it was observed that treatment with Kaftrio has a heterogeneous effect on CV risk factors, ameliorating some of them, such as chronic inflammation, and worsening others. Among the relevant factors determining CV risk, the capacity of HDL to promote cholesterol efflux (HDL-CEC), one of the main functions of this class of lipoproteins, has proven to be a better predictor than plasma HDL concentrations. In addition, the serum capacity to load macrophages with cholesterol (cholesterol loading capacity, CLC) represents an index of serum lipoproteins' pro-atherogenic potential.
This work aimed to evaluate the effect of six months of therapy with Kaftrio on serum lipoprotein functions, namely HDL-CEC and serum CLC, in 16 awCF, and in 8 sex and age-matched healthy controls. HDL-CEC through the main pathways was evaluated with a radioisotopic cell-based assay in specific cell models, and serum CLC was assessed fluorimetrically in human monocyte-derived macrophages THP-1.
Concerning plasma lipid profile, after treatment with Kaftrio, total cholesterol, LDL-C, and HDL-C significantly increased as compared to baseline (p<0.001, p<0.001, and p=0.023, respectively), reaching values comparable to those of healthy controls. Regarding HDL function, HDL-CEC mediated by the transporter ABCA1 was significantly lower in awCF at baseline compared to healthy controls (-14%, p=0.0142). Treatment with Kaftrio increased ABCA1 HDL-CEC compared to awCF at baseline (+7%, p=0.02499). Similarly, ABCG1 HDL-CEC was significantly lower in awCF at baseline compared to healthy controls (-22%, p=0.0218) while significantly higher after treatment compared to not treated awCF (+18%, p=0.0255). In both cases, Kaftrio restored HDL-CEC levels to values comparable to those of healthy controls.
No significant differences were found for serum CLC in awCF compared to healthy controls. Kaftrio did not have any significant impact on this parameter, despite the increased LDL-C levels observed after treatment.
In conclusion, Kaftrio treatment had a positive impact on the functional lipid profile as it increased ABCA1 and ABCG1 HDL-CEC without negatively affecting serum CLC. All these effects may contribute to reducing the CV risk in awCF.