Glycemia and Insulin Secretion in Cystic Fibrosis 2 Years After Elexacaftor/Tezacaftor/Ivacaftor: PROMISE-ENDO

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 substudy (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, and insulin secretory rates (deconvolution of C-peptide) and sensitivity (oral minimal model) prior to ETI and 12 to 18 months and 24-30 months 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 months n = 68 and at 24-30 months n = 58 completed OGTTs. At 24-30 months, fasting glucose (mg/dL) decreased (94 [92, 96] to 90 [88, 93], P = .02) in the subset not on insulin therapy (n = 61), but no differences in 1-hour or 2-hour glucose were found. HbA1c decreased from 5.8% (5.6%, 5.9%) to 5.5% (5.4%, 5.6%), P < .001 by 24-30 months. Although insulin sensitivity (mU/L-1 min-1) decreased (8.4 [7.2, 9.5] vs 6.8 [5.8, 7.9], P = .03), no changes in oral disposition index were found, P = .14.

Conclusion: After 2 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.

Figure 1.

Flow diagram of OGTT data collected at PROMISE Endocrine substudy baseline and follow-up visits. Abbreviations: mos, months; OGTT, oral glucose tolerance test.

Figure 2.

Sankey plots showing the percentage of participants in each glucose tolerance category at baseline and follow-up visits and the magnitude of change in category across visits, as illustrated by the size of the flow paths. Abbreviations: CFRD, cystic fibrosis–related diabetes; EGI, early glucose intolerance (with 1-hour glucose ≥ 155 mg/dL & 2-hour glucose < 140 mg/dL); IGT, impaired glucose tolerance; mos, months; NGT₁₅₅, normal glucose tolerance (with 1-hour glucose < 155 mg/dL and 2-hour glucose < 140 mg/dL); NGT₂₀₀, normal glucose tolerance (with 1-hour glucose < 200 mg/dL and 2-hour glucose < 140 mg/dL).

Figure 3.

Hemoglobin A1c (HbA1c) at baseline and after 12 to 18 and 24 to 30 months (mos) of ETI therapy, according to whether an individual was on insulin therapy (orange) or not (blue). Dashed lines at 5.7% and 6.5% represent prediabetes and diabetes thresholds, respectively. Triangles represent the mean HbA1c at baseline (5.8%), at 12 to 18 mos (5.5%), and at 24 to 30 mos (5.5%).

Figure 4.

Plasma glucose (left panel) and insulin secretory rates (right panel) according to baseline glucose tolerance status (normal glucose tolerance [NGT]; early glucose intolerance [EGI]; impaired glucose tolerance [IGT]; CF-related diabetes [CFRD]) at baseline visit (orange), 12 to 18 months (mos) post-ETI (teal), and 24 to 30 months post-ETI (dark blue). An asterisk denotes a statistically significant difference in OGTT glucose between baseline and follow-up (Wilcoxon matched-pairs signed-rank test).

Figure 5.

a. Percent predicted FEV₁ (ppFEV₁) at baseline and after 24-30 months (mos) of ETI therapy, according to whether an individual’s glucose tolerance status was categorized at baseline as normal (NGT, light blue), early intolerant (EGI, purple), impaired (IGT, orange), or diabetic (CFRD, navy blue), and whether their glucose tolerance status worsened, did not change, or improved from baseline to 24-30 mos. b. BMI z-score at baseline and after 24-30 months (mos) of ETI therapy, according to whether an individual’s glucose tolerance status was categorized at baseline as normal (NGT, light blue), early intolerant (EGI, purple), impaired (IGT, orange), or diabetic (CFRD, navy blue), and whether their glucose tolerance status worsened, did not change, or improved from baseline to 24-30 mos