(189) Impact of elexacaftor/tezacaftor/ivacaftor on Body Composition in a Small Cohort of Youth with Cystic Fibrosis

Background: The triple combination CFTR modulator elexacaftor (ELX)/tezacaftor (TEZ) /ivacaftor (IVA) has been shown to be highly effective in improving pulmonary function, body mass index (BMI) and reducing pulmonary exacerbations. With improvements in BMI and recent reports of obesity in the CF population, closer evaluations of the impact of ELX/TEZ/IVA on body composition may inform metabolic disease risk.

Methods: A secondary analysis of a prospective observational study assessing annual, frequently sampled OGTTs and dual energy X-ray absorptiometry (DXA) in people with CF ≥ 6 years of age. Inclusion: confirmed diagnosis of CF treated with ELX/TEZ/IVA and available DXA both before and after triple combination therapy. Exclusion: Use of medications affecting glucose homeostasis, including insulin; pulmonary exacerbations or admissions in the 8 weeks prior to the study visit; pregnancy. Paired t-tests were used to compare normally distributed variables and Wilcoxon signed rank test for non-normally distributed variables. Measurements of body composition by DXA included body free fat mass adjusted for height (FFMI) and total body fat mass adjusted for height (FMI). OGTTs with sampling at 0,10,30,60,90,120 min for glucose, insulin, and c-peptide were obtained. Integrated area under the curve (iAUC) for each was calculated. HOMA2 IR was calculated as an estimate of insulin sensitivity. Spirometry data from most recent clinic visit was obtained via chart review.

Results: Eight participants were included in the analysis. Median age was 22.1 years (IQR 16.2-28.2), 87.5% were male. The mean weight z-score was -0.52 (IQR -1.51,-0.31) and mean BMI z-score was -0.11(IQR -0.7,0.87). The median time on ELX/TEZ/IVA was 11 months (IQR 10.8-11.3). All participants were pancreatic insufficient and 50% Homozygous F508del. Table 1 presents the comparison of clinical outcomes before and after ELX/TEZ/IVA. Weight (kg) increased from 58.6 to 68.9 kg (p=0.01), while BMI z score did not change between visits. FMI increased (p=0.036) and FFMI did not change between visits. Glucose iAUC did not change (p=0.23). Insulin secretion as measured by iAUC and Cpeptide iAUC increased (p=0.02) and HOMA2 IR, as an index of insulin resistance increased (p=0.01).

Conclusions: In a small cohort of patients with CF treated with ELX/TEZ/IVA for less than year, weight and FMI increased while FFMI did not change. In addition, OGTT-derived estimates of insulin secretion (iAUC) and insulin resistance (HOMA2 IR) increased. Larger studies are needed to evaluate the effects of highly effective triple therapy on body composition, particularly body fat distribution and its association with insulin resistance in subjects with CF.

Acknowledgements: We thank the pediatric and adult Clinical Research Unit staff and patients from the participating CF Centers, University of Iowa, University of Colorado, University of Minnesota and Washington University School of Medicine in St Louis. This project is supported by CF Foundation Grant LARSON18A0

References: [1] 1. Middleton PG, Mall MA, Drevinek P, et al. elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019;381(19):1809-1819.

[2] 2. Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: A double-blind, randomized, phase 3 trial. 2019;394(10212):1940-1948.2