Glycemia and Insulin Secretion in Cystic Fibrosis Two Years After Elexacaftor/Tezacaftor/Ivacaftor: PROMISE-ENDO

Christine L Chan; Meghan Shirley Bezerra; Darko Stefanovski; Robert J Gallop; Rachel Walega; Scott H Donaldson; Carla A Frederick; Steven D Freedman; Daniel Gelfond; Lucas R Hoffman; Michael R Narkewicz; Steven M Rowe; Scott D Sagel; Sarah Jane Schwarzenberg; George M Solomon; Michael S Stalvey; Andrea Kelly

doi:10.1210/clinem/dgae857

Glycemia and Insulin Secretion in Cystic Fibrosis Two Years After Elexacaftor/Tezacaftor/Ivacaftor: PROMISE-ENDO

J Clin Endocrinol Metab. 2024 Dec 9:dgae857. doi: 10.1210/clinem/dgae857. Online ahead of print.

Authors

Christine L Chan¹, Meghan Shirley Bezerra², Darko Stefanovski³, Robert J Gallop⁴, Rachel Walega², Scott H Donaldson⁵, Carla A Frederick⁶, Steven D Freedman⁷, Daniel Gelfond⁸, Lucas R Hoffman^{9

10}, Michael R Narkewicz¹, Steven M Rowe^{11

12}, Scott D Sagel¹, Sarah Jane Schwarzenberg¹³, George M Solomon¹², Michael S Stalvey¹⁴, Andrea Kelly^{2

15}

Affiliations

¹ Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO.
² Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA.
³ New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, PA.
⁴ Department of Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
⁵ Department of Medicine, University of North Carolina at Chapel Hill, NC.
⁶ Jacobs School of Medicine and Biomedical Sciences of the University of Buffalo, NY.
⁷ Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
⁸ Western New York Pediatric Gastroenterology, NY.
⁹ Department of Pediatrics, University of Washington School of Medicine, Seattle, WA.
¹⁰ Department of Microbiology, University of Washington School of Medicine, Seattle, WA.
¹¹ Cystic Fibrosis Foundation, Bethesda, MD.
¹² Department of Medicine and the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
¹³ Department of Pediatrics, University of Minnesota Masonic Children's Hospital, Minneapolis, MN.
¹⁴ Endocrinology Consultant.
¹⁵ Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

PMID: 39657947
DOI: 10.1210/clinem/dgae857

Abstract

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective therapy that improves lung disease in people with cystic fibrosis (pwCF), but its effect on glucose tolerance and insulin secretion is unclear.

Methods: PROMISE is a multicenter prospective, observational study of ETI in pwCF ≥12 years and at least one F508del allele. The PROMISE Endocrine sub-study (PROMISE-ENDO) enrolled participants at 10 CF Centers where hemoglobin A1c (HbA1c) was collected and 3-hour oral glucose tolerance tests (OGTT) conducted to examine glucose tolerance, glucose excursions, insulin secretory rates (deconvolution of C-peptide) and sensitivity (oral minimal model) prior to ETI and 12-18 months (mos) and 24-30 mos following ETI initiation. Longitudinal mixed effects models were used to test within-subject ETI effects.

Results: At baseline, 79 participants completed OGTTs [39 (49%) male, median (IQR) age 19.6 (14.7, 27.3) years, BMI z-score 0.12 (-0.51, 0.65)]. At 12-18 mos n=68 and at 24-30 mos n=58 completed OGTTs. At 24-30 mos, fasting glucose (mg/dL) decreased [94 (92, 96) to 90 (88, 93), p=0.02] in the subset not on insulin therapy (n=61), but no differences in 1-hr or 2-hr glucose were found. HbA1c (%) decreased from 5.8 (5.6, 5.9) to 5.5 (5.4, 5.6), p<0.001 by 24-30 mos. Although insulin sensitivity (mU/L-1.min-1) decreased [8.4 (7.2, 9.5) vs. 6.8 (5.8, 7.9), p=0.03], no changes in oral disposition index were found, p=0.14.

Conclusions: After two years of ETI, fasting glucose and HbA1c showed modest decreases. Glucose tolerance varied, and overall measures of insulin secretion did not deteriorate.

Keywords: cystic fibrosis; cystic fibrosis-related diabetes; elexacaftor/tezacaftor/ivacaftor; hemoglobin A1c; modulator; oral glucose tolerance test.

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