(46) Lipid Trends on Highly Effective Modulators in Cystic Fibrosis

Background: There are few reports of cardiovascular disease (CVD) in people with cystic fibrosis (PwCF). However, with advances like highly effective modulator therapy (HEMT), PwCF are living longer with increasing exposure to CF related diabetes (CFRD) and are increasingly overweight or obese. All of these factors increase the risk of CVD. Prior studies of serum lipids in PwCF prior to the advent of HEMT typically demonstrated low levels of total cholesterol (TC), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). It is not known whether HEMT may change serum lipid profiles in PwCF, perhaps due to altered absorption or metabolism.

Methods: We addressed this knowledge gap using the Carolina Data Warehouse to identify PwCF >18 years old at the University of North Carolina (UNC) Cystic Fibrosis Center with available lipid panel data within 5 years prior to starting ivacaftor (Kalydeco) or elexacaftor/tezacaftor/ivacaftor (Trikafta) and at any timepoint thereafter. Retrospective chart review after obtaining Institutional Review Board (IRB) approval was performed. Exclusion criteria included solid organ transplantation or type 1 diabetes. The primary endpoint was change in TC; secondary endpoints included changes in HDL, TC/HDL ratio, change in BMI, and a new diagnosis of hypertension. Unadjusted mean changes in TC were assessed via paired t-tests. Of note, available samples were not consistently collected in the fasting state.

Results: We identified 42 patients meeting study criteria: 27 (64%) were female; 24 (57%) had CFRD; 12 (29%) had CF liver disease; 36 (86%) were pancreatic insufficient. Mean age at HEMT initiation was 40 years old (range: 16 to 73). On average, there was a three-year interval between the pre- and post-HEMT lipid panel, and 17 months between HEMT initiation and the post-HEMT lipid panel. We noted significant increases in TC, LDL, and TC/HDL ratio (Table 1) after HEMT. There was no significant change in HDL. BMI rose significantly. At baseline, 9 patients had diagnoses of hypertension; 3 additional patients were diagnosed after starting HEMT.

Conclusions: Our results are limited by their retrospective nature, variable time between lipid assessments and exposure to HEMT. However, in this small sample, the increases in TC, TC/HDL radio, and LDL are potentially clinically meaningful as higher values are associated with increased CVD risk. HDL, a cardioprotective lipid, did not change. If confirmed in larger, more tightly controlled studies, this could suggest long-term exposure to HEMT may increase CVD risk. This knowledge may influence health screening practices. When combined with other CVD risk factors, lipid lowering therapy may be considered for some PwCF on HEMT.

Acknowledgements: This work was supported by P30 DK065988, and DESPOT20B0. We acknowledge the assistance of the NC Translational and Clinical Sciences (NC TraCS) Institute, which is supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through Grant Award Number UL1TR002489.

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