(15) Promise: Glucose excursion & insulin secretion following 12-18 months of highly effective modulator therapy

Background: Clinical observations, case series, and registry data identified improved glucose tolerance, better insulin secretion, and less cystic fibrosis-related diabetes (CFRD) diagnoses with ivacaftor. Inspired by these data, this study was designed to test the impact of clinically-prescribed elexacaftor/tezacaftor/ivacaftor (E/T/I) upon glucose intolerance and insulin secretion and sensitivity.

Methods: Three-hour, 10 sample oral glucose tolerance tests (OGTT) were performed at baseline and 12-18 months at 10 designated endocrine sub-study centers of PROMISE, a 56-center prospective, observational study of E/T/I in people with CF aged >12y and at least one F508del mutation. Rapid-acting insulin was withheld for the subset treated with insulin. Glucose tolerance (GT) was defined by glucose (mg/dL) as: normal (NGT), early intolerance (EGI): 60-min >155 & 120-min< 140, impaired (IGT): 120-min >140 & < 200, CFRD: 120-min >200 and hypoglycemia as glucose<65 mg/dL. GT, HbA1C, and OGTT glucose (0, 60, 120-min), insulin sensitivity (SI), and 0-30 min glucose and insulin secretory rates (ISR) incremental areas-under-the-curve (iAUC₃₀) were compared between baseline and follow-up using mixed effect ordinal or linear models (fixed effect: visit; random effect: subject) and to further test for relationships with age, BMI-Z, and FEV₁%-predicted.

Results: Baseline and follow-up OGTT were available in 65 of 69 participants (33F/32M, median age 18.3y [min-max: 12-51.9], 13 were treated with insulin. HbA1C% and fasting glucose improved, but no differences in GT were found (Table): 17/57 with abnormal GT improved while 9/41 without CFRD worsened; hypoglycemia rates were not different. 60 and 120-min glucose were not different. For the subset of participants for whom complete data were available (n=51), no differences in iAUC₃₀Glucose, iAUC₃₀ISR, iAUC₃₀ISR: iAUC₃₀Glucose, or SI were found. These results persisted after adjustment for age, BMI, FEV1%-predicted, and CFRD history, and while CFRD was associated with lower iAUC₃₀ISR: iAUC₃₀Glucose, no interaction between CFRD and visit was found.

Conclusions: In these preliminary analyses, OGTT-related glucose excursion and insulin secretion did not improve with 12-18 months of clinically prescribed E/T/I despite modest decreases in HbA1C; however, HbA1C better reflects longer-term glycemia. The impacts of more prolonged E/T/I on insulin secretion and glucose tolerance remain to be determined.

Acknowledgements: This work was supported by the Cystic Fibrosis Foundation [PROMISE-OB-18] and the National Institute of Health UL1 TR001878 (University of Pennsylvania Center for Human Phenomic Science) and P30 DK19525 (University of Pennsylvania Diabetes Research Center).

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