(209) Metabolic changes post elexacaftor/tezacaftor/ivacaftor in a Northern Ireland Population with Cystic Fibrosis

Background: Dyslipidaemia is prevalent in people with cystic fibrosis (pwCF). CFTR modulators are drugs which target the defective CFTR protein. Elexacaftor/tezacaftor/ivacaftor was approved for use in Northern Ireland (NI) in 2020. Metabolic effects of elexacaftor/tezacaftor/ivacaftor at a population level are unknown. We therefore reviewed several metabolic parameters including lipid profile and HbA1c in our adult population prescribed elexacaftor/tezacaftor/ivacaftor.

Methods: Electronic Care Records (2011-2022) of 306 adult PWCF were examined for metabolic parameters including lipid profile and HbA1c. Those prescribed elexacaftor/tezacaftor/ivacaftor were examined pre and post introduction.

Results: Median age of our population was 33 (18- 78) years. Fifty two percent of our population were male, 36% pancreatic sufficient and 24% have CF diabetes (CFD). Seventy one records included complete lipid profiles and HbA1c, 109 were excluded as lipid profiles were unavailable pre and post elexacaftor/tezacaftor/ivacaftor. Average length of time on elexacaftor/tezacaftor/ivacaftor was 9.5 months. Fifty one percent were male, median age 33 (19 -65) years.

Table 1 reports metabolic parameters pre and post the introduction of elexacaftor/tezacaftor/ivacaftor. Mean total cholesterol, HDL-C, and LDL-C levels all increased following introduction (all p< 0.05). Mean Chol/HDL ratio showed an upwards trend but there was no statistical difference (p= 0.391) and triglycerides remained unchanged (p=0.491). The proportion of pwCF with abnormal total cholesterol levels, abnormal LDL-C levels and abnormal total chol/HDL ratios all increased following introduction (all p< 0.05). The proportion of pwCF with abnormal HDL-C levels (p=0.001) and abnormal HBA1c levels (p=0.006) decreased following elexacaftor/tezacaftor/ivacaftor introduction. The proportion with abnormal triglycerides were unchanged (p=0.326).

We have previously reported an increased prevalence of dyslipidaemia among adults with CF.Here we show an increase in dyslipidaemia in our population prescribed elexacaftor/tezacaftor/ivacaftor over a relatively short period of time. It is unknown whether these levels will continue to increase and what the long term effects will be. One single centre study in America had similar results but smaller numbers. The link between dyslipidaemia and cardiovascular disease in the general population is well-established. Mean HbA1c and those with abnormal HbA1c was decreased following elexacaftor/tezacaftor/ivacaftor. HbA1c can reflect blood glucose levels and risk of CFD.

Conclusions: In our cohort of adults with CF, the use of elexacaftor/tezacaftor/ivacaftor was associated with increasing lipid levels and increasing proportion of patients with abnormal lipids. Given the increasing life expectancy for those with CF and the widespread use of CFTR modulators more research is needed into the long term effects on metabolic parameters and cardiovascular risk in pwCF.

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