(6) Decline in HbA1c during the First Year on Elexacaftor/Tezacaftor/Ivacaftor in the Danish CF Population

Background: In cystic fibrosis (CF), elexacaftor/tezacaftor/ivacaftor has a remarkable effect on lung function, but whether it has an impact on glucose tolerance including CF related diabetes (CFRD) is not clear. We aimed to study both the effect of elexacaftor/tezacaftor/ivacaftor on glycated hemoglobin (HbA1c) in the Danish national CF population and the changes in use of insulin in a CFRD sub-population during the first year of treatment.

Methods: The entire Danish CF population is followed in either of two CF centers, which measured HbA1c at baseline, three, six, nine and twelve months after the initiation of elexacaftor/tezacaftor/ivacaftor. All treated individuals ≥12 years with a baseline sample and ≥1 follow-up sample were included in the study. During consultations with individuals with CFRD before and twelve months after initiation of treatment, use of insulin, hypoglycemic events, and, if available, continuous glucose monitoring (CGM) data from the past 30 days were obtained. Change in HbA1c three and nine months post treatment initiation were assessed for each group of age (12-25, 26-35, 36-45, 46-80 years), sex, glucose tolerance status (normal (NGT): < 7.8, impaired (IGT): 7.8-11.0, CFRD: >11.0 mM 2-hour glucose), and previous modulator treatment (naïve, first generation modulator) in mixed models using splines. The models included interaction between the concerned covariate and treatment time and were adjusted for the above-mentioned covariates. Changes in use of insulin and CGM parameters (i.e., covariance, average blood glucose, time below (< 3.9 mM) and above ( >10.0 mM) normal range) were assessed in paired Wilcoxon signed rank tests.

Results: Among 298 individuals with CF, HbA1c was 43.3 mmol/mol at baseline and after three months of treatment HbA1c was 1.9 mmol/mol lower [95%CI: -1.3; -2.4 mmol/mol, p< 0.001] and after nine months HbA1c was reduced by 2.7 mmol/mol [95%CI: -2.2; -3.1 mmol/mol, p< 0.001]. In all age, sex, glucose tolerance, and previous treatment groups HbA1c had declined significantly after three months and even more after nine months. The youngest individuals seemed to have the smallest decline in HbA1c (12-25 years: -1.8 mmol/mol [95%CI: -0.7; -3.0 mmol/mol, p< 0.001]), while the decline seemed more pronounced in individuals between 36-45 years of age (-3.4 mmol/mol [95%CI: -1.6; -5.2 mmol/mol, p< 0.001]) after nine months. The decline was independent of glucose tolerance status (NGT: -2.4 mmol/mol [95%CI: -1.3; -3.5 mmol/mol, p< 0.001] and CFRD: -2.8 mmol/mol [95%CI: -1.8; -3.8 mmol/mol, p< 0.001]) (Figure 1). In 26 individuals with CFRD, HbA1c declined, but we did not see a significant change in insulin use after twelve months; long-acting insulin: -2.0 IE/day [95%CI: -5.0; 3.5 IE/day], p=0.207 and short-acting insulin: -4.3 IE/day [95%CI: -12.0; 0.0 IE/day], p=0.054. The weekly number of hypoglycemic events did not change (0.2 [95%CI: -3.2; 1.8, p=0.811]), neither did the CGM parameters (i.e., covariance, average blood glucose, time above and below range).

Conclusions: In the Danish CF population, HbA1c continued to decline over nine months of elexacaftor/tezacaftor/ivacaftor treatment irrespective of age and diabetes status. Among 26 individuals with CFRD, we were unable to detect a significant change in CFRD treatment and regulation. We speculate that other factors than insulin secretion (i.e., reduced inflammation or more physical activity) might contribute to the reduction HbA1c.

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